METHOD OF TREATING PATIENTS COADMINISTERED A FACTOR Xa INHIBITOR AND VERAPAMIL

ABSTRACT

The present disclosure in various embodiments teaches methods of treating patients in need of treatment with a Factor Xa inhibitor, and who are also concomitantly administered verapamil.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of U.S. application Ser. No. 15/438,393, filed on Feb. 21, 2017, which claims priority to U.S. Provisional Application No. 62/298,555, filed Feb. 23, 2016, the disclosures of each of which are herein incorporated by reference in its entirety for all purposes.

FIELD

In various embodiments, the present invention relates to the field of blood coagulation. In particular embodiments, the present invention relates to novel methods of administration and dosing of rivaroxaban in the treatment of patients who require anticoagulant therapy, for example treatment with a Factor Xa inhibitor.

BACKGROUND

Maintenance of normal haemostasis—between bleeding and thrombosis—is subject to complex regulatory mechanisms. Uncontrolled activation of the coagulant system or defective inhibition of the activation processes may cause formation of local thrombi or embolisms in vessels (arteries, veins) or in heart cavities. This may lead to serious thromboembolic disorders, such as myocardial infarct, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive disorders, pulmonary embolisms or deep venous thromboses.

Anticoagulant drugs target various procoagulant factors in the coagulation pathway. Presently there are numerous anticoagulant drugs which are widely available. One new class of anticoagulant drugs is direct Factor Xa inhibitors, which play a central role in the cascade of blood coagulation by inhibiting Factor Xa directly.

Rivaroxaban is a Factor Xa inhibitor drug used to treat disorders including deep vein thrombosis (DVT) and pulmonary embolism (PE). It is also used to help prevent strokes or serious blood clots in people who have atrial fibrillation.

Use of rivaroxaban, however, presents considerable risk to patients whereby higher than expected blood concentrations of rivaroxaban can cause serious adverse events, most notably elevated rates of internal bleeding/hemorrhage. Conversely, any under dosing of the drug leaves a patient at risk of potentially fatal clotting events.

Accordingly, it is one object of the present invention to provide novel methods of rivaroxaban dosage control.

SUMMARY OF THE DISCLOSURE

In some embodiments, the present disclosure is directed to a method of treating a patient in need of treatment with a Factor Xa inhibitor and who is concomitantly administered verapamil, comprising administering a dose of rivaroxaban which is a reduced dose (e.g., about 99.5% to about 0%) relative to the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil. In various embodiments, the patient in need of treatment with a Factor Xa inhibitor has normal renal function, and in still other embodiments, the patient has renal insufficiency (mild, moderate or severe as described herein).

In some embodiments, the present disclosure is directed to a method of treating a patient in need of treatment with a Factor Xa inhibitor, e.g., a patient with renal insufficiency (mild, moderate or severe as described herein) comprising administering a dose of rivaroxaban which is a reduced dose (e.g., about 99.5% to about 0%) relative to the dose recommended for an otherwise identical (or the same) patient who does not have renal insufficiency.

In some embodiments, the present disclosure is directed to treatment of a patient with a medical condition requiring treatment with a Factor Xa inhibitor, for example a medical condition selected from the group consisting of atrial fibrillation; deep vein thrombosis; patients undergoing major orthopedic surgery; deep vein thrombosis prophylaxis, deep vein thrombosis prophylaxis after abdominal surgery; deep vein thrombosis prophylaxis after hip replacement surgery; deep vein thrombosis prophylaxis after knee replacement surgery; deep vein thrombosis recurring event; heart attack; prevention of thromboembolism in atrial fibrillation; pulmonary embolism; pulmonary embolism recurring event; thromboembolic stroke prophylaxis; venous thromboembolism; prevention of ischemic stroke; recurring myocardial infarction; antiphospholipid antibody syndrome; sickle cell disease; prevention and treatment of venous thromboembolism in cancer patients; cancer associated thrombosis; cancer patients with central line associated clots in the upper extremity; reducing post-discharge venous thromboembolism risk in medically ill patients; treating young children with venous thrombosis (6 months-5 years); treatment of arterial or venous thrombosis in children from birth to less than 6 months; thrombophylaxis in pediatric patients 2 to 8 years of age after the fontan procedure; valvular heart disease and atrial fibrillation; patients with atrial fibrillation with bioprosthetic mitral valves; treatment of symptomatic isolated distal deep vein thrombosis; superficial vein thrombosis; prevention of thrombosis after replacement of the aortic valve with a biological valve prosthesis; prevention of recurrence of stent thrombosis and cardiovascular events in patients with atrial fibrillation complicated with stable coronary artery disease; treatment of splanchnic vein thrombosis; prevention of recurrent thrombosis in patients with chronic portal vein thrombosis; prevention of recurrent symptomatic venous thromboembolism in patients with symptomatic deep vein thrombosis or pulmonary embolism; acute ischemic stroke with atrial fibrillation; venous thromboembolism prophylaxis in patients undergoing non-major orthopedic surgery; reducing the risk of major thrombotic vascular events in subjects with peripheral artery disease undergoing peripheral revascularization procedures of the lower extremities; prevention of cardiovascular events in patients with nonvalvular atrial fibrillation scheduled for cardioversion; reducing the risk of death, myocardial infarction, or stroke in participants with heart failure and coronary artery disease following an episode of decompensated heart failure; preventing major cardiovascular events in coronary or peripheral artery disease; reducing the risk of cardiovascular death, myocardial infarction, or stroke in patients with recent acute coronary syndrome; prevention of the composite of stroke or systemic embolism in patients with rheumatic valvular heart disease (RVHD) with atrial fibrillation or flutter who are unsuitable for vitamin K antagonist therapy, or in patients with RVHD without AF or Flutter with at least one of the following: Left atrial enlargement ≥5.5 cm, Left atrial spontaneous echo contrast, left atrial thrombus, frequent ectopic atrial activity (>1000/24 hours) on Holter ECG; prevention of restenosis after infrainguinal percutaneous transluminal angioplasty for critical limb ischemia; and decreasing the risk of cardiovascular disease, myocardial infarction, revascularization, ischemic stroke, and systemic embolism. In other embodiments, the present invention is directed to treating a condition for which a Factor Xa inhibitor is indicated, and for which a calcium channel blocker is indicated, including any of the conditions described herein such as reducing the risk of stroke and systemic embolism in patients with non valvular atrial fibrillation, treating deep vein thrombosis (DVT), treating pulmonary embolism (PE), reducing the risk of DVT, and reducing the risk of PE, the prophylaxis of DVT which leads to PE in patients undergoing knee or hip replacement therapy, and the management of essential hypertension. In still other embodiments, the present invention is directed to treating a condition for which a factor Xa inhibitor is indicated, including reducing the risk of stroke and systemic embolism in patients with non valvular atrial fibrillation, treating deep vein thrombosis (DVT), treating pulmonary embolism (PE), reducing the risk of DVT, and reducing the risk of PE, the prophylaxis of DVT which leads to PE in patients undergoing knee or hip replacement therapy. Patients treated in this manner can have normal renal function, or can be mildly, moderately, or severely renally impaired.

In some embodiments, the present disclosure is directed to treatment of a patient with a medical condition requiring treatment with a calcium channel blocker (in conjunction with a Factor Xa inhibitor), including management of essential hypertension, treatment of hypertension, treatment of pulmonary hypertension, prevention and treatment of recurrent and paroxysmal supraventricular tachycardia, management of supraventricular tachycardia, treatment of atrial tachycardia and junctional tachycardia, treatment of cerebral vasospasm, treatment of hypertrophic cardiomyopathy, treatment of chronic stable angina pectoris, treatment of unstable angina pectoris, management of Prinzmetal variant angina, ventricular rate control in atrial fibrillation/flutter, prevention of cluster headache, prevention of migraine, prevention of myocardial infarction in patients with preserved left ventricular function, management of manic manifestations of bipolar disorder, treatment of Raynaud's disease, treatment of coronary artery disease, treatment of subarachnoid hemorrhage, treatment of Dravet Syndrome, beta cell survival therapy in Type I diabetes, treatment of vestibular migraine, treatment of chronic subjective dizziness, treatment of erectile dysfunction, prevention of keloid recurrence, treatment of refractory epilepsy, treatment of refractory meningioma, treatment of chronic heart failure secondary to non-ischemic cardiomyopathy, treatment of relapsed or refractory Hodgkin lymphoma, treatment of Marfan Syndrome, treatment of treatment-resistant mania, prevention of kidney disease in diabetic patients, treatment of Metabolic Syndrome, and treatment of hypoglycemia following gastric bypass.

In some embodiments, the present disclosure is directed to a method of treating a patient concomitantly administered rivaroxaban and verapamil, wherein the dose of rivaroxaban administered to the patient is less than the rivaroxaban dose recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil.

In some embodiments, the present disclosure is directed to a method of treating a patient concomitantly administered rivaroxaban and verapamil, wherein the dose of rivaroxaban administered to the patient is 0% to about 99.5% of the rivaroxaban dose recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil.

In any of the various embodiments disclosed herein, the patient who is concomitantly administered rivaroxaban and verapamil can have normal renal function.

In any of the various embodiments disclosed herein, the patient who is concomitantly administered rivaroxaban and verapamil can be mildly renally impaired.

In any of the various embodiments disclosed herein, the patient who is concomitantly administered rivaroxaban and verapamil can have moderate renal impairment.

In any of the various embodiments disclosed herein, the patient who is concomitantly administered rivaroxaban and verapamil can have severe renal impairment.

In any of the various embodiments disclosed herein, the maximum prothrombin time of said patient concomitantly administered rivaroxaban and verapamil ranges from about 20 to about 30 seconds.

In any of the various embodiments disclosed herein, the C_(max) plasma concentration of rivaroxaban for the patient concomitantly administered rivaroxaban and verapamil is less than about 317 ng/mL.

In any of the various embodiments disclosed herein, the AUC of rivaroxaban for the patient concomitantly administered rivaroxaban and verapamil is in the range of about 1668(μg/L)·h-3792(μg/L)·h.

In some embodiments disclosed herein, the dose of rivaroxaban administered to the patient who is concomitantly administered rivaroxaban and verapamil ranges from about 0 mg to about 19.9 mg, or any intervening values as disclosed herein, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

In some embodiments disclosed herein, the dose of rivaroxaban administered to the patient who is moderately renally impaired and concomitantly administered rivaroxaban and verapamil ranges from about 0 mg to about 14.9 mg, or any intervening values as disclosed herein, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 15 mg.

In some embodiments disclosed herein, the dose of rivaroxaban administered to the patient who is concomitantly administered rivaroxaban and verapamil is about 0 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, or about 17.5 mg, the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg, and the daily dose of verapamil ranges from about 100 to about 480 mg.

In some embodiments disclosed herein, the dose of rivaroxaban administered to the patient who is concomitantly administered rivaroxaban and verapamil is about 0 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, 12.5 mg, or less than about 15 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 15 mg and the daily dose of verapamil is 100 to 480 mg.

In some embodiments disclosed herein, the patient who is concomitantly administered rivaroxaban and verapamil is not renally impaired. In some embodiments disclosed herein, the patient who is concomitantly administered rivaroxaban and verapamil is mildly renally impaired. In some embodiments disclosed herein, the patient who is concomitantly administered rivaroxaban and verapamil is moderately renally impaired. In some embodiments disclosed herein, the patient who is concomitantly administered rivaroxaban and verapamil is severely renally impaired.

In some embodiments disclosed herein, the dose of rivaroxaban administered to the patient who is concomitantly administered rivaroxaban and verapamil is selected to generate a prothrombin time of said patient ranges from about 20-30 seconds. In still further embodiments, the dose of rivaroxaban is 10 mg to 15 mg.

In some embodiments disclosed herein, the dose of rivaroxaban administered to the patient who is concomitantly administered rivaroxaban and verapamil is less than the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil, and wherein the C_(max) of rivaroxaban in said patient is no more than about 317 ng/mL.

In some embodiments, the dose of rivaroxaban administered is such that the AUC (AUC_(inf) or AUC_(ss)) and/or C_(max) (C_(max) for a single dose or steady state) values of rivaroxaban in the treated patient population does not exceed target values, as described herein in Tables 9-124. The rivaroxaban dose is designed such that a particular statistical PK parameter characterizing the particular patient population (e.g., maximum, mean of highest 3 patients, 90% confidence interval upper boundary, median, arithmetic mean, geometric mean, 90% confidence level lower boundary, or minimum of the AUC_(inf) and/or C_(max),) does not exceed the selected target value. So, for example, for a patient with mild renal impairment, concomitantly administered rivaroxaban and verapamil (Table 9), the dose of rivaroxaban intended to provide an AUC_(inf) of less than 3,792 μg·hr/L for the patient in a population with the highest exposure (“maximum”) (Target 1) would be a dose of no more than about 8.7 mg rivaroxaban.

BRIEF DESCRIPTIONS OF THE FIGURES

FIG. 1 shows a correlation between plasma concentrations of rivaroxaban and Prothrombin Time (“PT”) in subjects with no renal insufficiency. Data were measured on Day 1 and Day 15 of the study.

FIG. 2 shows a correlation between plasma concentrations of rivaroxaban and PT in subjects with mild renal insufficiency. Data were measured on Day 1 and Day 15 of the study.

FIG. 3 shows the ranges of steady state rivaroxaban AUC values for various single dose rivaroxaban treatments (10842, 10993, 10999, 12359, 12680, 11273, 10989, 11938, studies), and single dose rivaroxaban plus Verapamil treatments. Abbreviations in the figure are N: Normal renal function; MRI: mild renal impairment; P1: 20 mg rivaroxaban only; P3: 20 mg rivaroxaban and 360 mg Verapamil. The lines represent the geometric mean and for the numbered studies the top and bottom represent +/−1 standard deviation. For the Normal and MRI groups by study period, the lines represent the geometric mean and the top and bottom represent the sample maximum and minimum.

FIG. 4 shows the 90% confidence level rivaroxaban AUC value (single 20 mg dose) (Label “A”), steady state rivaroxaban AUC value as described in the Clinical Pharmacology approval documents for Rivaroxaban and separately the 10 mg steady state dose in the presence of a strong CYP3A4/Pgp inhibitor (Label “B”) from the same report. The third item, (Label “C”) shows the upper 90% confidence interval value for rivaroxaban administered under fed conditions as determined in clinical study 10989. These values are compared to the ranges of AUC measured by the present inventors under various conditions. Abbreviations in the figure are SS: steady state; CI: confidence interval; AUC inf: area under the curve extrapolated to infinity; N: Normal renal function; MRI: mild renal impairment; P1: a single 20 mg rivaroxaban only; P3: a single 20 mg rivaroxaban plus 360 mg Verapamil.

FIG. 5 shows the relationship between the steady state AUC values and the risk of major bleeding.

DETAILED DESCRIPTION

While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter.

Throughout the disclosure, singular forms such as “a,” “an,” and “the” are often used for convenience. However, it should be understood that the singular forms are intended to include the plural, except when context or an explicit statement indicates that the singular alone is intended.

Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device or the method being employed to determine the value, or the variation that exists among the samples being measured. In some embodiments, the term “about” means within 5% of the reported numerical value. When used in conjunction with a range or series of values, the term “about” applies to the endpoints of the range or each of the values enumerated in the series, unless otherwise indicated.

As used herein, the term “concomitant” refers to the co-administration of two or more drugs. In some embodiments, concomitant administration includes the administration of two or more drugs at substantially the same time, either as a mixture (e.g., in a coformulation), or as separate doses. In some embodiments, concomitant administration also includes the sequential administration of two or more drugs, wherein both drugs are simultaneously present at clinically relevant levels in a patient's plasma.

As used herein, the term “pharmacokinetics” refers to a drug's movement into, through, and out of the body, including: the drug's absorption, bioavailability, tissue distribution, metabolism, and excretion.

As used herein, C_(max) refers to peak plasma concentration of a therapeutic agent as it relates to a particular drug dose (e.g. rivaroxaban dose).

As used herein. T_(max) refers to the time required to reach peak concentration.

As used herein, C_(ave) refers to average plasma concentration of a therapeutic agent under a particular drug dosing schedule (e.g. rivaroxaban dosing schedule).

As used herein, C_(min) refers to the minimum plasma concentration of a therapeutic agent under a particular drug dosing schedule (e.g. rivaroxaban dosing schedule).

In some embodiments, the present disclosure teaches that the pharmacokinetic effects of a drug can be compared based on area under the curve (AUC) values. The pharmacokinetic AUC of a drug is calculated by taking the integral (area under the curve) of the concentration of a drug against time.

As used herein, “treating” in the context of treating a condition refers to reducing or eliminating the symptoms of a condition, reducing the risk of, or preventing the patient from experiencing the symptoms of a condition. For example, treatment of a condition with rivaroxaban can reduce the risk of stroke or systemic embolism in patients, reducing the risk of recurrence of deep vein thrombosis and pulmonary embolism, the prophylaxis of deep vein thrombosis, etc.

As used herein, AUC_(0-∞) or AUC_(inf) refers to the area under the curve extrapolated to infinity, after administration of a single dose of drug. AUC_(ss) refers to the AUC under steady state conditions, and approximates AUC_(inf).

As used herein, the term “pharmacodynamics” refers to a drug's effect(s) on the body, including: receptor binding, postreceptor effects, and chemical interactions. In some embodiments, a drug's pharmacodynamics determines the onset, duration, and intensity of that drug's effect.

As used herein, the term “prothrombin time” (PT) refers to a blood test that measures how long it takes blood to clot. In some embodiments, a prothrombin time test can be used to measure of a patient's haemostasis. In some embodiments, PT can be used to measure the effectiveness or exposure to a blood clotting drug. Persons having skill in the art sometimes interchangeably refer to a PT test as an INR. However, since the INR is calibrated specifically for warfarin, PT measurements suitable for rivaroxaban would not be comparable to the INR standards for warfarin. Additionally, PT measurements are subject to variability based on the test reagent and laboratory test ranges determined by each institution.

Rivaroxaban was developed with the premise that it would not require the type of monitoring required for conventional anticoagulant drugs such as warfarin (Coumadin). PT/INR tests are conventionally used specifically for monitoring vitamin K antagonists such as warfarin. Alternative tests, such as the activated partial thromboplastin time (APTT) are conventionally used to monitor the use of unfractionated heparin. However, as discussed in Favaloro et al., Biochemia Medica 2012; 22(3): 329-41, the PT/INR and APTT tests are not suitable for monitoring patients treated with rivaroxaban because inconsistent results are obtained for rivaroxaban depending on factors such as the reagents used, and the tests are either too sensitive or insensitive to be useful. In addition, such tests are not calibrated for rivaroxaban, and therefore there is no standardized measure for the activity of rivaroxaban in such patients. While the literature suggests that suitable tests could be developed, presently there are no validated or generally recognized methods suitable for monitoring the use of rivaroxaban in hospital laboratories or available to healthcare providers. See also, Xarelto® Package Insert (Revised August 2016, section 5.7). Consequently, there are no current methods available for monitoring the dose titration of rivaroxaban. Indeed, the sponsor of the rivaroxaban NDA maintains that dose titration is not appropriate in most patient populations (Application Number: 022406Orig1s000 Clinical Pharmacology and Biopharmaceutics Review(s), Addendum to Apr. 6, 2009 Review). See Hillarp et al., Journal of Thrombosis and Haemostasis, 9: 133-139; Favarolo et al., Biochemia Medica 2012; 22(3): 329-41; Nielsen et al., Clin. Res. Cardiol. 22 Nov. 2014 (published online); and Mueck et al., Clin. Pharmacokinet (2014) 53:1-16.

As used herein, E_(max) refers to peak effect of a therapeutic agent related to a particular drug dose (e.g. rivaroxaban dose).

As used herein, the term “AUEC” refers to area under the effect curve. In some embodiments, the pharmacodynamic AUEC of an effect for a particular drug is calculated by taking the integral (area under the curve) of the drug's measured effect against time.

In some embodiments, the AUEC of rivaroxaban is calculated based on the integral of the prothrombin time effect a rivaroxaban dose has on a patient over time.

As used herein, “renal impairment” means the individual has a clinically relevant level of renal function which is less than levels of renal function generally considered to be normal. Levels of renal function, renal sufficiency or renal impairment can be determined using any of the methods known in the art or described herein. Currently, one common method for determining the level of renal sufficiency in an individual is determining creatinine clearance (CL_(Cr)) in the individual using the Cockcroft-Gault equation. In some embodiments, the present disclosure teaches alternative methods of measuring renal impairment, for example those described in U.S. Published App. 2012/022787.

As disclosed herein, the individual's actual body weight, ideal body weight, or otherwise adjusted body weight can be used in the equation. In some embodiments, the following are criteria for determining the level of renal sufficiency using creatinine clearance (CL_(Cr)) and the Cockcroft-Gault equation:

Normal renal function > or =80 mL/min

Mild renal impairment=50-79 mL/min

Moderate renal impairment=30-49 mL/min

Severe renal impairment <30 mL/min

Newer criteria for determining the level of renal sufficiency using CL_(Cr) define the cut-offs between normal, and mild-severe renal impairment using slightly different CL_(Cr) ranges:

Normal renal function > or =90 mL/min

Mild renal impairment=60-89 mL/min

Moderate renal impairment=30-59 mL/min

Severe renal impairment=15-29 mL/min

Kidney failure <15 mL/min

A “patient” is a living organism, typically a human.

For nearly all FDA approved drugs, the “recommended” dose (or doses) of the drug are determined based on the plasma level (or range of plasma levels) of the drug required to provide the desired clinical effect(s) and/or avoid undesirable side effects. The recommended dose(s) of a particular drug are those recognized in the art as suitable for treating a patient with particular physical characteristics (or within a range of particular characteristics), and are thus the dose(s) provided in the package insert for the drug. Thus, in various embodiments, the methods of the present disclosure are directed to adjustments or changes in the dosing of rivaroxaban relative to the FDA “recommended” dose, e.g., in the package insert for rivaroxaban, as suitable for treating a patient with particular physical characteristics. Thus, as used herein, the “recommended dose” for rivaroxaban is distinct from doses which may be disclosed by particular physicians for particular patients. Depending on the specific pharmacokinetics and pharmacodynamics of the drug, the recommended dose may vary depending on one or more physical characteristics of the patient, for example age, gender, weight, body mass index, liver metabolic enzyme status (e.g., poor or extensive metabolizer status), disease state, etc. Xarelto® (rivaroxaban) is currently sold in three FDA-approved doses: 10 mg (e.g., NDC 50458-580-30), 15 mg (e.g., NDC-50458-578-30), and 20 mg (e.g., NDC 50458-579-30).

As provided in the rivaroxaban package insert (as revised August 2016), the 15 mg and 20 mg tablets should be taken with food, and the 10 mg tablets taken with or without food. For patients with nonvalvular atrial fibrillation, with CL_(Cr)>50 mL (normal to mild renal impairment), the 20 mg dose with the evening meal is recommended. For such patients with CL_(Cr) 15-50 (severe to moderate renal impairment), the 15 mg dose with the evening meal is recommended. For patients with DVT, PE, and to reduce the risk of recurrence of DVT and PE, it is recommended that patients be administered 15 mg twice daily with food for the first 21 days, then 20 mg once daily with food for the remaining treatment. For the prophylaxis of DVT following hip or knee replacement surgery, 10 mg once daily is recommended with or without food.

With respect to drug-drug interactions, the rivaroxaban package insert recommends avoiding concomitant use of rivaroxaban with combined P-gp and strong CYP3A4 inhibitors and inducers—that is, rivaroxaban and the combined P-gp and strong CYP3A4 inhibitors or inducers should not be coadministered; rather, one or the other drug should be discontinued. Although concomitant administration of rivaroxaban with drugs such as erythromycin, which is considered in the Xarelto® package insert to be a combined P-gp and moderate CYP3A4 inhibitor, has been observed to increase exposure to rivaroxaban, the package insert indicates that no precautions are necessary in such coadministration if the change in exposure is not expected to affect bleeding risk (see section 7.1 of the package insert), but that otherwise rivaroxaban should not be used unless the potential benefit justifies potential risk (see section 7.5 of the package insert). However, various studies discussed herein have shown that there are as yet no suitable assays for monitoring rivaroxaban dosing or assessing potential risk. (see e.g., Favarolo et al., Biochemia Medica 2012; 22(3): 329-41; Xarelto® Package Insert). Also, concomitant administration of rivaroxaban with combined P-gp and strong CYP3A4 inhibitors should be avoided—i.e., one or the other drugs should be eliminated.

Thus, although drug-drug interactions with rivaroxaban are known (e.g., elevated exposure to rivaroxaban in the presence of combined P-gp and CYP3A4 inhibitors), only in the case of coadministration of rivaroxaban and combined P-gp and strong CYP3A4 inhibitors is it necessary to eliminate (i.e., avoid) the use of rivaroxaban. Indeed, until the present disclosure, those of skill in the art have not identified clinically relevant interactions between rivaroxaban and commonly prescribed medications by virtue of rivaroxaban's multiple elimination pathways. (See W. Mueck et al., Clin Pharmacokinet (2014) 53:1-16). Thus, to-date, studies of drug-drug interactions with rivaroxaban have only identified coadministration of rivaroxaban with combined P-gp and strong CYP3A4 inhibitors (or strong inducers) as requiring any modification of rivaroxaban dosing, and in such instances it is recommended that the rivaroxaban (or alternatively the strong inhibitor/inducer) be eliminated entirely from the treatment.

As discussed herein, the methods of the present disclosure provide for an adjustment of the rivaroxaban dose relative to the recommended dose that patient if the patient was not concomitantly administered verapamil. Alternatively as discussed herein, the methods of the present disclosure provide for an adjustment of the rivaroxaban dose relative to the recommended dose for an otherwise identical patient not concomitantly administered verapamil. As used herein, the term an “otherwise identical patient who is not concomitantly administered verapamil” refers to a patient whose physical characteristics relevant to drug (e.g., rivaroxaban) dosing are expected to be substantially the same as that of the patient being treated with a reduced rivaroxaban dose according to the presently disclosed methods—except for the concomitant administration of verapamil. In some embodiments, the otherwise identical patient will be of substantially the same age, sex, and body weight. In some embodiments, the substantially identical patient will also have substantially identical renal function and drug metabolism. In some embodiments, the recommended dose of the otherwise identical patient who is not concomitantly administered verapamil is the dose that would have been recommended to that same patient, had that patient not been concomitantly administered verapamil.

All terms not specifically defined herein should be given the ordinary meaning that a person of skill in the art at the time of the invention would ascribe to them.

In some embodiments, the present disclosure is directed to methods of treating a patient in need of treatment with a Factor Xa inhibitor such as rivaroxaban. In some embodiments, a non-limiting list of the medical conditions which require treatment with a Factor Xa inhibitor (e.g., rivaroxaban) include: atrial fibrillation; deep vein thrombosis; patients undergoing major orthopedic surgery; deep vein thrombosis prophylaxis, deep vein thrombosis prophylaxis after abdominal surgery; deep vein thrombosis prophylaxis after hip replacement surgery; deep vein thrombosis prophylaxis after knee replacement surgery; deep vein thrombosis recurring event; heart attack; prevention of thromboembolism in atrial fibrillation; pulmonary embolism; pulmonary embolism recurring event; thromboembolic stroke prophylaxis; venous thromboembolism; prevention of ischemic stroke; recurring myocardial infarction; antiphospholipid antibody syndrome; sickle cell disease; prevention and treatment of venous thromboembolism in cancer patients; cancer associated thrombosis; cancer patients with central line associated clots in the upper extremity; reducing post-discharge venous thromboembolism risk in medically ill patients; treating young children with venous thrombosis (6 months-5 years); treatment of arterial or venous thrombosis in children from birth to less than 6 months; thrombophylaxis in pediatric patients 2 to 8 years of age after the fontan procedure; valvular heart disease and atrial fibrillation; patients with atrial fibrillation with bioprosthetic mitral valves; treatment of symptomatic isolated distal deep vein thrombosis; superficial vein thrombosis; prevention of thrombosis after replacement of the aortic valve with a biological valve prosthesis; prevention of recurrence of stent thrombosis and cardiovascular events in patients with atrial fibrillation complicated with stable coronary artery disease; treatment of splanchnic vein thrombosis; prevention of recurrent thrombosis in patients with chronic portal vein thrombosis; prevention of recurrent symptomatic venous thromboembolism in patients with symptomatic deep vein thrombosis or pulmonary embolism; acute ischemic stroke with atrial fibrillation; venous thromboembolism prophylaxis in patients undergoing non-major orthopedic surgery; reducing the risk of major thrombotic vascular events in subjects with peripheral artery disease undergoing peripheral revascularization procedures of the lower extremities; prevention of cardiovascular events in patients with nonvalvular atrial fibrillation scheduled for cardioversion; reducing the risk of death, myocardial infarction, or stroke in participants with heart failure and coronary artery disease following an episode of decompensated heart failure; preventing major cardiovascular events in coronary or peripheral artery disease; reducing the risk of cardiovascular death, myocardial infarction, or stroke in patients with recent acute coronary syndrome; prevention of the composite of stroke or systemic embolism in patients with rheumatic valvular heart disease (RVHD) with atrial fibrillation or flutter who are unsuitable for vitamin K antagonist therapy, or in patients with RVHD without AF or Flutter with at least one of the following: Left atrial enlargement ≥5.5 cm, Left atrial spontaneous echo contrast, left atrial thrombus, frequent ectopic atrial activity (>1000/24 hours) on Holter ECG; prevention of restenosis after infrainguinal percutaneous transluminal angioplasty for critical limb ischemia; and decreasing the risk of cardiovascular disease, myocardial infarction, revascularization, ischemic stroke, and systemic embolism.

Atrial fibrillation (AF) is a common cardiac disorder that is characterized by a disruption of the normal electrical impulses generated by the sinoatrial (SA) node. The resulting disorganized electrical impulses lead to an irregular heartbeat and abnormal blood flow.

AF is also a significant stroke risk factor. The characteristic lack of coordinated atrial contraction in AF can result in clot formation in the atrium, and particularly the left atrial appendage of the heart. The increased stasis of blood in the atrium due to loss of mechanical function (i.e. contraction), combined with poorly understood changes in the thrombogenicity of the atrial endocardial surface in AF is thought to be the primary basis for clot formation in the left atrium and left atrial appendage in AF.

If the blood clot leaves the atria and becomes lodged in an artery in the brain, a stroke results. Diagnosed AF is associated with a four- to five-fold increase in stroke risk (Wolf P A, Abbott R D, Kannel W B, Arch Intern Med. 1987 September; 147(9):1561-4; Stroke. 1991 August; 22(8):983-8). Approximately 15% of strokes in the U.S. occur in individuals previously diagnosed with AF. It is believed that even more strokes are associated with undiagnosed AF (Tayal, et al., Neurology. 2008 Nov. 18; 71(21):1696-701).

Patients diagnosed with AF often receive dual treatment of calcium channel blockers for their heart arrhythmia and anticoagulants to reduce the risk of stroke.

Rivaroxaban (Formula I), which is commercially available under the trade name Xarelto®, is disclosed in U.S. Pat. No. 7,157,456 (B2), U.S. Pat. No. 7,585,860 (B2), and U.S. Pat. No. 7,592,339 (B2), each of which is hereby incorporated in their entireties for all purposes.

Rivaroxaban is a Factor Xa inhibitor drug used to treat thrombosis-related disorders, among other conditions as disclosed herein. Rivaroxaban activity is mediated though its inhibition of Factor Xa, which in turn reduces the conversion of prothrombin to thrombin. It is also used to help prevent strokes or serious blood clots in people who have atrial fibrillation.

Use of rivaroxaban however, presents risks related to improper dosing. The FDA Draft Guidance on Rivaroxaban (Recommended September 2015) states that rivaroxaban demonstrates a “steep exposure-response relationship for both efficacy and safety” and therefore should “refer to the guidance on warfarin sodium.” In other words, rivaroxaban is recognized as a drug having a narrow therapeutic index (e.g., meeting nearly all if not all the proposed FDA definitional terms of a Narrow Therapeutic Index drug; [Quality and Bioequivalence Standards for Narrow Therapeutic Index Drugs, Lawrence X Yu, Office of Generic Drugs, GPhA 2011 Fall Technical Workshop]), such that higher than expected plasma concentrations of rivaroxaban can cause serious adverse events, including internal bleeding/hemorrhage, and underdosing leaves a patient at risk of potentially fatal clotting events. Careful monitoring of patients treated with rivaroxaban is made even more difficult by the current lack of specific antidotes against rivaroxaban overdosing, the lack of specific treatments with proven efficacy for severe bleeding linked with the use of rivaroxaban, and the lack of a routine coagulation test suitable for monitoring patients treated with rivaroxaban (as discussed herein). Conventional methods for reducing plasma levels which are useful for other anticoagulants such as dabigatran (e.g. haemodialysis and FDA-approved specific antidote idarucizumab) are not effective for rivaroxaban, because rivaroxaban cannot be eliminated from the body through dialysis and there is no specific antidote for rivaroxaban. (Bleeding with dabigatran, rivaroxaban, apixaban. No antidote, and little clinical experience.” Prescrire Int. 2013 June; 22(139):155-9; PRAXBIND® Product Insert).

The risks associated with incorrectly dosing rivaroxaban have caused the drug to be placed on the Institute for Safe Medication Practices (ISMP) list of high-alert medications as a drug with “heightened risk of causing significant potential harm.” (Institute for Safe Medication Practices (ISMP) “ISMP List of High-Alert Medications in Acute Care Settings” https://www.ismp.org/tools/highalertmedications.pdf (Accessed October 2015)).

In some embodiments, rivaroxaban dosing is compared in terms of its pharmacokinetic responses in different patients or patient populations, and in response to different situations. For example, in some embodiments, the present disclosure teaches methods of adjusting rivaroxaban dosing in patients concomitantly administered rivaroxaban and verapamil, relative to otherwise identical (or the same) patients not concomitantly administered verapamil, in order to provide a particular rivaroxaban AUC_(inf), AUC_(ss), C_(max), C_(max ss) or C_(ave) (or a range of values of such parameters) in said patient or patient population.

In other embodiments, rivaroxaban dosing is compared in terms of its pharmacokinetic and pharmacodynamics effects. For example, in some embodiments, the present disclosure teaches methods of adjusting rivaroxaban dosing in patients concomitantly administered rivaroxaban and verapamil, relative to otherwise identical (or the same) patients not concomitantly administered verapamil, in order to provide a particular prothrombin time or decrease the incidence rate of adverse events (or range of values of such parameters) in said patient or patient population.

In some embodiments, the present disclosure teaches that rivaroxaban pharmacokinetics and pharmacodynamics are at least partially a consequence of the drug's excretion/secretion and metabolism, particularly when coadministered with verapamil.

Approximately one-third (36%) of each rivaroxaban dose is eliminated in the patient's urine as unprocessed active drug. Of this 36% elimination, 30% is eliminated through active renal secretion, while the remaining 6% is eliminated though glomerular filtration. (Weinz C, Schwarz T, Kubitza D, et al. Metabolism and excretion of rivaroxaban, an oral, direct Factor Xa inhibitor, in rats, dogs and humans. Drug Metab Dispos. 2009; 37:1056-64; Kubitza et al. Effects of renal impairment on the pharmacokinetic, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Brit J of Clinical Pharma 70:5 703-712).

Renal impairment can also have effects on the pharmacodynamics of rivaroxaban. Even moderate changes in rivaroxaban AUC and half-life (t_(1/2)) can lead to significant changes in haemostasis. In subjects with mild, moderate, and severe renal impairment administered a 10 mg dose of rivaroxaban, the AUEC for Factor Xa inhibition was 1.5-fold, 1.86-fold, and 2.0-fold higher than in healthy subjects, respectively. (Kubitza et al. Effects of renal impairment on the pharmacokinetic, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Brit J of Clinical Pharma 70:5 703-712). In this work Kubitza et al. did not evaluate patients administered 20 mg doses, or evaluate drug-drug interactions. However, even in such studies, Kubitza et al. found that such increases in rivaroxaban exposure were unlikely to be clinically relevant, and that safety profiles were similar in patients with differing levels of renal impairment. Thus, Kubitza et al. did not recognize any need to adjust rivaroxaban doses in such patients.

However, the present applicants have found that the recommended rivaroxaban dose should be adjusted in patients in need of Factor Xa inhibitor treatment who are coadministered verapamil. Thus in some embodiments, the present disclosure is directed to methods of treating patients in need of Factor Xa inhibitor treatment, said method comprising adjusting rivaroxaban dosing in response to changes in a patient's renal function.

Renal secretion of rivaroxaban is partially regulated by the Permeability glycoprotein (P-gp) pathway. P-gp transporters are found in the luminal membrane of several tissues, including the blood-brain barrier, the small intestine excretory cells, hepatocytes, and kidney proximal tubule epithelia. P-gp expression on intestinal epithelial cells regulates cellular uptake and absorption of drugs into enterocytes, whereas expression of P-gp transporters on the surface of hepatocytes and renal tubular cells regulates the elimination of drugs into the bile and urine (Wessler et al. The P-glycoprotein transport system and cardiovascular drugs. J. American College of Cardiology Vol 61:25).

In some embodiments, the present disclosure teaches that P-gp induction or inhibition can result in different pharmacokinetic and pharmacodynamic responses to fixed rivaroxaban doses. For example, in some embodiments, the present disclosure teaches that P-gp inhibition can lead to rivaroxaban overdosing due to decreased renal excretion of the drug.

P-gp inhibition is thought to involve modulation by 1 of 4 pathways: direct inhibition of binding sites that block the transport of substrates, ATP binding inhibition, ATP hydrolysis, or coupling of ATP hydrolysis to the translocation of the substrate.

Unfortunately, molecules that are modulators of P-gp substrates do not share any obvious structural characteristics, and it is thus difficult to predict the effect of concomitant administration of a drug on P-gp function (Wessler et al. The P-glycoprotein transport system and cardiovascular drugs. J. American College of Cardiology Vol 61:25.)

Moreover, different drugs may interact differentially with P-gp, which results in a distinct mechanism of modulation of P-gp activity. As shown by Polli et al., Journal of Pharmacology and Experimental Therapeutics, vol. 299(2), 620-628 (2001), various assays of P-gp inhibition can give widely varying results. Polli et al. describe three different P-gp assays: the monolayer efflux assay (using Caco-2 cells), the ATPase and calcein-AM assays. Of the three, the monolayer efflux assay is considered the most reliable because it is a direct measurement of efflux. Polli et al. demonstrated that verapamil does not show efflux (i.e., is not a P-gp substrate) in the monolayer efflux assay, but provides positive results in the ATPase and calcein-AM assays.

Gnoth et al., Journal of Pharmacology and Experimental Therapeutics, vol. 338(1), 372-380 (2011) evaluated the P-gp transport characteristics of rivaroxaban, and rivaroxaban in the presence of potential P-gp inhibitors such as clarithromycin and erythromycin. The authors observed that erythromycin did not inhibit P-gp-mediated efflux of rivaroxaban across cell monolayers in vitro—in fact, erythromycin increased the efflux of rivaroxaban in a statistically significant manner. Thus, erythromycin and verapamil utilize distinct mechanisms in their interaction with and regulation of P-gp activity, which could lead to differing inhibitory effects. Gnoth et al. concluded that the impact of P-gp inhibition, alone, had only a marginal effect on the pharmacokinetics of rivaroxaban, and that only strong P-gp inhibitors at high doses might result in drug-drug interactions.

Approximately two-thirds of each rivaroxaban dose is subject to metabolic degradation via the liver's oxidative and hydrolytic pathways.

At least three functional CYP3A proteins exist in humans. The CYP3A4 monooxygenase is the predominant cytochrome P450 in human liver and small bowel. The protein displays a broad substrate specificity and it metabolizes more than 60% of all drugs that are currently in use, including contraceptive steroids, antidepressants, benzodiazepines, immunosuppressive agents, imidazole antimicotics, and macrolide antibiotics (Cholerton, Trends Pharmacol Sci 13 (1992), 434-9; Ketter, J Clin Psychopharmacol 15 (1995), 387-98).

Rivaroxaban metabolic clearance is catalyzed by CYP3A4/5, CYP2J2, and CYP-independent mechanisms. (Kubitza et al. Effects of renal impairment on the pharmacokinetic, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Brit J of Clinical Pharma 70:5 703-712). The CYP3A4 isozyme in particular, accounts for approximately 18% of the rivaroxaban clearance. (Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013; 76:455-66).

In some embodiments, the present disclosure teaches that variations in CYP3A4 activity can result in different pharmacokinetic and pharmacodynamic responses to fixed rivaroxaban doses. A considerable variation in the CYP3A4 content and catalytic activity has been described in the general population. For example, studies have shown that the metabolic clearance of the CYP3A4 substrates exhibit a unimodal distribution with up to 20-fold variability between individual patients. This result is also born out in direct activity studies which demonstrated that the activities of the CYP3A4 protein in liver biopsies vary up to 30-fold between individuals (Westlind, Biochem Biophys Res Commun 259 (1999), 201-205).

In order to assess the effects of combined P-gp and CYP3A4 inhibitors on the metabolism of rivaroxaban, a study was conducted to examine the effects of co-administration of rivaroxaban with erythromycin, a combined moderate CYP3A4 inhibitor and P-gp inhibitor. Erythromycin is known to be eliminated mainly in the bile, and 2-15% renally (unchanged). However, based on this study, no dose adjustment for rivaroxaban in the presence of such a combined inhibitor was found to be necessary. Similar results were obtained for clarithromycin and fluconazole, suggesting significant interactions with other drugs in this category are unlikely. (Mueck et al. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. British J. of Clinical Pharma 76:3 455-466).

On the contrary, the FDA-approved rivaroxaban label states that rivaroxaban use should be avoided (i.e., should not be administered at all) in patients receiving “concomitant combined P-gp and moderate CYP3A4 inhibitors” unless “the potential benefit justifies the potential risk.” However, since, as discussed herein there is no clinically standardized test methodology for evaluating the pharmacodynamics of rivaroxaban as there are for other, conventional anticoagulants such as warfarin and heparin (i.e., PT/INR or APTT tests), there is no clinically acceptable or useful methodology for evaluating the potential risk.

In some embodiments, the present disclosure is directed to methods of adjusting rivaroxaban doses in response to CYP3A4 induction or inhibition. In some embodiments, the present invention thus teaches that the concomitant administration of other drugs can alter CYP3A4 expression levels (via induction or repression). For example, some known inducers of CYP3A4 expression include drugs such as the glucocorticoid dexamethasone, the antibiotic rifampicin, and the antimycotic clotrimazole. Like the regulation of P-gp secretion however, the effect of any drug on CYP3A4 activity is difficult to predict.

In addition to metabolism by CYP3A4, 14% of rivaroxaban is metabolized by CYP2J2 (((Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br. J. Clin. Pharmacol. 2013; 76:455-66). It has been shown that verapamil can inhibit greater than 95% of metabolism by CYP2J2 in vitro, while erythromycin did not demonstrate significant inhibition of CYP2J2 activity (Lee C A et al. “Identifying a Selective Substrate and Inhibitor Pair for the Evaluation of CYP2J2 Activity.” Drug Metabolism and Disposition 2012 vol. 40 pp943-951). The clinical implications of the potential inhibition of CYP2J2-mediated metabolism of rivaroxaban by verapamil are as yet unknown.

Thus in some embodiments, the present disclosure is directed to methods of treating patients in need of Factor Xa inhibitor treatment, said method comprising adjusting rivaroxaban dosing (as described herein) in response to changes in a patient's altered liver drug metabolism.

Verapamil is a calcium channel blocker used in the treatment of angina, arrhythmia, and essential hypertension among other uses, for example as disclosed herein. Verapamil is extensively metabolized to a number of metabolites, at least one of which (norverapamil) retains significant activity and is itself a P-gp inhibitor. Approximately 70% is excreted in the urine (mainly as metabolites, but about 4% unchanged), and approximately 16% in the feces.

Verapamil is a popular drug, used daily by millions of older patients with heart issues. The prevalent use of the drug has caused it to be listed in the World Health Organizations (WHO) list of essential medicines (found at http://www.who.int/medicines/publications/essentialmedicines/en/).

In some embodiments, the present disclosure is directed to treatment of a patient with a medical condition requiring treatment with a calcium channel blocker such as verapamil (in conjunction with a Factor Xa inhibitor), including management of essential hypertension, treatment of hypertension, treatment of pulmonary hypertension, prevention and treatment of recurrent and paroxysmal supraventricular tachycardia, management of supraventricular tachycardia, treatment of atrial tachycardia and junctional tachycardia, treatment of cerebral vasospasm, treatment of hypertrophic cardiomyopathy, treatment of chronic stable angina pectoris, treatment of unstable angina pectoris, management of Prinzmetal variant angina, ventricular rate control in atrial fibrillation/flutter, prevention of cluster headache, prevention of migraine, prevention of myocardial infarction in patients with preserved left ventricular function, management of manic manifestations of bipolar disorder, treatment of Raynaud's disease, treatment of coronary artery disease, treatment of subarachnoid hemorrhage, treatment of Dravet Syndrome, beta cell survival therapy in Type I diabetes, treatment of vestibular migraine, treatment of chronic subjective dizziness, treatment of erectile dysfunction, prevention of keloid recurrence, treatment of refractory epilepsy, treatment of refractory meningioma, treatment of chronic heart failure secondary to non-ischemic cardiomyopathy, treatment of relapsed or refractory Hodgkin lymphoma, treatment of Marfan Syndrome, treatment of treatment-resistant mania, prevention of kidney disease in diabetic patients, treatment of Metabolic Syndrome, and treatment of hypoglycemia following gastric bypass.

In particular, verapamil has become an effective treatment for atrial fibrillation. Verapamil has been shown to prolong the effective refractory period within the AV node to slow Atrioventricular (AV) conduction in a dose-dependent manner. This property accounts for the ability of verapamil to slow the ventricular rate in patients with chronic atrial flutter or atrial fibrillation, reducing the subjective sensation of palpitations (Johansson and Olsson. 1984 Long-term oral treatment with high doses of verapamil in lone atrial fibrillation. Clin. Cardiol. 7, 163-170). Typical daily doses of verapamil for such patients range from about 40 mg to about 480 mg, often divided in 3 to 4 equal doses during the day. Alternatively, extended release verapamil formulations can be administered once a day, in daily doses of 100 mg to 400 mg, (including 40 mg, 100 mg, 200 mg, 300 mg, and 400 mg). Verapamil is available in various dosage forms including without limitation extended-release capsules (100, 120, 180, 200, 240, 300, and 360 mg), extended-release tablets (120, 180, and 240 mg), immediate release tablets (40, 80, and 120 mg doses), IV solutions (5 mg/2 mL and 10 mg/4 mL), and as combination formulations (e.g., extended release trandolapril/verapamil HCl tablets, 1 mg/240 mg, 2 mg/180 mg, 2 mg/240 mg, 4 mg/240 mg).

Thus patients with atrial fibrillation are often prescribed verapamil to treat heart palpitations, and rivaroxaban to reduce the risk of stroke.

The present disclosure is at least partially based on the inventors' discovery that the concomitant administration of verapamil and rivaroxaban leads to an unexpectedly increased risk of rivaroxaban overdosing and adverse drug effects. Without wishing to be bound by any one theory, the present inventors believe that administration of verapamil and rivaroxaban leads to an unexpected clinically significant drug-drug interaction that negatively impacts the metabolic and excretion clearance of rivaroxaban and can lead to increased adverse events. Thus, in at least some embodiments, the present invention is a method of reducing the side effects (increased bleeding, such as gastrointestinal bleeding; or alternatively reducing the risk of clotting if the rivaroxaban dosing is discontinued) when verapamil is coadministered with rivaroxaban, by adjusting the rivaroxaban dose to less than the currently recommended dose (i.e., the dose(s) recommended on the Xarelto® package insert as amended 8/2016) as described herein. For example, when the recommended rivaroxaban dose is 20 mg, the adjusted dose of rivaroxaban ranges from 0 mg to about 19.9 mg (e.g., about 0 mg, about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 17.5 mg, about 18 mg, about 19 mg, or about 19.9 mg); or when the recommended rivaroxaban dose is 15 mg, the adjusted dose of rivaroxaban ranges from about 0 mg to about 14.9 mg (e.g., about 0 mg, about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, or about 14.9 mg); or when the recommended rivaroxaban is 10 mg, the adjusted dose of rivaroxaban ranges from about 0 mg to about 9.9 mg (e.g., about 0 mg, about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, or about 9.9 mg).

Likewise, for any of the adjusted rivaroxaban doses enumerated above, the daily verapamil dose ranges from about 100 mg to about 480 mg per day (e.g., about 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg or about 480 mg), whether administered as a divided dose (e.g., 2-4 times daily) or a single extended release dose. For some patients treated according to the present disclosure, the patient is not concomitantly administered verapamil (i.e., the verapamil dose is 0 mg/day).

Verapamil is classified as an inhibitor of cytochrome P450 CYP3A4 and also as an inhibitor of the transporter permeability-glycoprotein (P-gp). Verapamil has been classified by the FDA as a moderate inhibitor of CYP3A4, but has less of an inhibitory effect on excretion of edoxaban, a similar Factor Xa inhibitor, than erythromycin, which is also viewed by the FDA as a moderate CYP3A4 inhibitor. Furthermore, erythromycin and verapamil are metabolized (cleared) from the body of a patient in substantially differently ways. Erythromycin is mainly metabolized by demethylation in the liver by the CYP3A4 enzyme, and is eliminated primarily in the bile, with little renal excretion (2-15% unchanged drug). In contrast, as discussed above, verapamil undergoes extensive hepatic metabolism, and its metabolites are excreted primarily in the urine. Additionally, some metabolites (i.e., norverapamil and metabolite D-703) also have inhibitory potential toward P-gp (Pauli-Magnus C et al. “Characterization of the Major Metabolites of Verapamil as Substrates and Inhibitors of P-glycoprotein.” J Pharmacol Exp Ther 2000; 293:376-382). The clinical relevance of inhibition of P-gp by the metabolites of verapamil is as yet unknown. Thus, verapamil and erythromycin are quite different in their respective metabolic characteristics, particularly renal clearance and the mechanisms by which they interact with P-gp, and thus studies of rivaroxaban/erythromycin co-administration would not be expected to provide clinical insights directly relevant to any drug-drug interactions between rivaroxaban and verapamil.

In some embodiments, the present disclosure teaches that the concomitant administration of verapamil leads to a reduction in the body's clearance (metabolism and excretion) of rivaroxaban. Moreover, atrial fibrillation is a disease associated with older patients, with a median age of about 70 years old (Fuster V., et al., Circulation. 2006). Thus in some embodiments, the present disclosure teaches that reduced rivaroxaban clearance due to concomitant administration of verapamil is also likely exacerbated by age-related impairment and/or renal impairment of patients receiving the drug.

In some embodiments, the present disclosure teaches that the concomitant administration of verapamil and rivaroxaban is associated with higher proportion of adverse events, for example compared to otherwise identical (or the same) patient populations in which verapamil is not administered.

In some embodiments, the present disclosure teaches that rivaroxaban pharmacokinetics are at least partially affected by changes in a patient's CYP3A4 metabolism and P-gp secretion. The present disclosure demonstrates however, that general knowledge about the secretion and metabolism pathways of rivaroxaban are not sufficiently clear to predict whether any particular drug would have undesirable drug interaction(s) with rivaroxaban, or that such undesirable interaction(s) could be addressed effectively by the specific dose adjustments of rivaroxaban provided herein, rather than, e.g., eliminating one or both drugs from the patient's treatment. Indeed, the general knowledge in the art indicates that, except for strong combined CYP3A4/P-gp inhibitors, any noted change in rivaroxaban exposure is not clinically relevant, and coadministration of rivaroxaban and strong combined CYP3A4/P-gp inhibitors is to be avoided entirely.

This document has already described that P-gp inhibitors do not share any obvious structural characteristics that could be used to predict a drug's effect on P-gp secretion (Wessler et al. The P-glycoprotein transport system and cardiovascular drugs. J. American College of Cardiology Vol 61:25). Similarly (despite many structural modeling efforts), the molecular structure of a drug is not dispositive of a drug's effect on CYP3A4 inhibition (Sridhar et al. Insights on cytochrome P450 enzymes and inhibitors obtained through QSAR studies. Molecules. 17(8): 9283-9305). It would therefore be difficult, if not impossible, for a person having ordinary skill in the art to predict a drug's effect on liver metabolism or renal secretion solely based on its structure.

Moreover, in some embodiments, the present invention also teaches that even empirical evidence of a drug's inhibition of CYP3A4 metabolism and/or P-gp secretion, is still not predictive of whether the drug will have a clinically relevant effect on rivaroxaban exposure.

Previous studies have demonstrated that concomitant administration of other CYP3A4 and P-gp inhibitors did not produce clinically relevant effects on rivaroxaban exposure or the prevalence of adverse events. For example, other studies have shown that concomitant administration of rivaroxaban and erythromycin (a moderate CYP3A4 and strong P-gp inhibitor) produced a 34% rivaroxaban exposure increase. Similarly, concomitant administration of rivaroxaban with clarithromycin (another strong CYP3A4 inhibitor and moderate P-gp inhibitor) produced a 54% rivaroxaban exposure increase. The concomitant administration of rivaroxaban and fluconazole (a moderate CYP3A4 inhibitor) produced a 42% rivaroxaban exposure increase (Mueck et al. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013; 76:455-66). Thus the present disclosure teaches that not all CYP3A4 and P-gp inhibitors exhibit clinically relevant drug-drug interactions with rivaroxaban.

Verapamil and erythromycin are also dosed quite differently clinically. Erythromycin is an antibiotic useful for the treatment of various bacterial infections, and is usually administered for relatively short periods of time, e.g. 1-2 weeks. In contrast, verapamil is typically administered to treat chronic conditions such as hypertension, angina pectoris, cardiac arrhythmias, etc. and is administered over much longer periods of time. These conditions are common comorbidities and indications for use in patients that would also require treatment with rivaroxaban.

The observation that patients concomitantly administered rivaroxaban represented 30% of the reported rivaroxaban serious bleeding adverse events, despite accounting for only 22% of the total population receiving rivaroxaban (see Example 1) was unexpected in view of the teachings of the prior art which suggested no clinically relevant drug-drug interactions existed between verapamil and rivaroxaban. For example, Xarelto's® (rivaroxaban) own product insert concludes that concomitant use of rivaroxaban with verapamil did not result in increased patient bleeding (see ROCKET AF trial in section 7.5 of Xarelto® product insert (revised August 2016). Additionally, a poster presented on Nov. 8, 2015 at the American Heart Association 2015 Scientific Sessions concluded that use of non-dihydropyridine calcium channel blockers such as verapamil with rivaroxaban was not associated with an increased risk of non-major clinically relevant or major bleeding compared to subjects on non-dihydropyridine calcium channel blockers and warfarin (see Poster S4081—Efficacy and Safety of Rivaroxaban versus Warfarin in Patients Taking Non-dihydropyridine Calcium Channel Blockers: Results from the ROCKET-AF Trial, presented Nov. 8, 2015, American Heart Association, Scientific Sessions 2015, and published at http://www.abstractsonline.com/pp8/#!/3795/presentation/37668).

Moreover, the present disclosure also teaches that the increased incidence of adverse events was not common to all CYPA34 and P-gp inhibitors, but was rather unexpectedly specific to verapamil. For example, in some embodiments, the present disclosure teaches that concomitant administration of rivaroxaban and erythromycin (another moderate CYP3A4 inhibitor and strong P-gp inhibitor) is not associated with increased serious bleeding adverse events.

The present invention's discovery of the need to adjust the dose of rivaroxaban when coadministered with verapamil was also unexpected based on, among other factors, the lack of any perceived clinically relevant drug-drug interactions between rivaroxaban and substrates of CYP enzymes (e.g., Mueck et al.), the expected weaker P-gp inhibition of verapamil compared to erythromycin, verapamil's previous history of safe concomitant administration with other anticoagulants, including other direct Factor Xa inhibitors. For example, previous studies reviewing the interaction between edoxaban (an oral direct Factor Xa inhibitor) and verapamil, concluded that their co-administration did not lead to any increased bleeding or other adverse events (Mendell et al., Drug-drug interaction studies of cardiovascular drugs involving p-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxban, an oral Factor Xa inhibitor. Am. J. Cardiovasc Drugs (2013) 13:331-342). Accordingly, the label for SAVAYSA™ (edoxaban) does not suggest reduced dosing for patients concomitantly administered with verapamil (SAVAYSA™ product insert, Highlights of prescribing information (revised September 2016), found at http://dsi.com/prescribing-information-portlet/getPIContent?productName=Savaysa). Moreover, the SAVAYSA™ product insert shows that concomitant administration of edoxaban and verapamil has a smaller impact on edoxaban exposure compared to concomitant administration edoxaban with erythromycin, as shown by the lower GMR values for the C_(max) and AUC parameters of verapamil compared to erythromycin (e.g., FIG. 12.1 of the SAVAYSA™ product insert). Thus, to the extent edoxaban/verapamil coadministration may be predictive of the drug-drug interactions expected for coadministered rivaroxaban/verapamil, the effects of verapamil coadministration would be expected to be appreciably less than for erythromycin coadministration. However, the SAVAYSA™ product insert does not recommend dose adjustment of edoxaban when coadministered with either erythromycin or verapamil.

Similarly, the only clinically significant drug-drug interactions identified in the ELIQUIS® (apixaban) package insert (revised September 2015) are with strong dual CYP3A4 and P-gp inhibitors such as ketoconazole, itraconazole, and, and clarithromycin.

In addition, the dabigatran (PRADAXA®) label, another anticoagulant, states that interaction of dabigatran with various P-gp inhibitors (e.g., verapamil, amiodarone, quinidine, clarithromycin and ticagrelor) does not require a dose adjustment of PRADAXA®, and that this conclusion should not be extrapolated to other P-gp inhibitors, further indicating that P-gp inhibition is unpredictable and one of skill in the art would not use the study of a particular drug to directly inform dosing instructions for another drug. For this reason, studies of interactions between, for example, rivaroxaban and erythromycin is not a good predictor for interactions between e.g. rivaroxaban and verapamil.

In addition, to the extent that the Xarelto® (rivaroxaban) Package Insert indicates that concomitant use of combined P-gp and CYP3A4 inhibitors is contraindicated or should be avoided (due to reduced elimination of rivaroxaban), there are a number of known alternative anticoagulants, such as apixaban, edoxaban, or dabigatran, better safety and/or efficacy profiles in patients with reduced clearance. See for example Nielsen et al., Clin. Res. Cardiol. 22 Nov. 2014 (published online) which refers to apixaban as a first line choice for patients with impaired renal elimination due to its comparable efficacy and favorable safety profile.

The current FDA approved dosing scheme for rivaroxaban includes a once-daily 10-20 mg dose. Specifically, patients with nonvalvular atrial fibrillation, deep vein thrombosis, or pulmonary embolism, are recommended to take a once-daily 20 mg oral dose with the evening meal, while patients with deep vein thrombosis following hip or knee replacement surgery are recommended to take a once-daily 10 mg dose with or without food. Xarelto's® (rivaroxaban) product insert does not currently recommend a dose reduction with verapamil (https://www.xareltohcp.com/shared/product/xarelto/prescribing-information.pdf).

In some embodiments, the present disclosure is directed to methods of treating a patient in need of treatment with a Factor Xa inhibitor and who is concomitantly administered verapamil, said method comprising administering a reduced dose of Factor Xa inhibitor relative to the recommended dose of Factor Xa inhibitor for an otherwise identical (or the same) patient who is not concomitantly administered verapamil. In particular embodiments, the Factor Xa inhibitor is rivaroxaban.

In some embodiments, the present disclosure is directed to the administration of a reduced rivaroxaban dose, in which the reduced rivaroxaban dose is about 0%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, 99%, or 99.5% of the rivaroxaban dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil, including all ranges therebetween.

Thus in some embodiments, the present disclosure is directed to the administration of a reduced rivaroxaban dose, in which the reduced rivaroxaban dose is between about 0%-99.5% of the recommended dose for an otherwise identical (or the same) patient who is not concomitantly administered verapamil, and all ranges and subranges within as described herein. For example, in some embodiments, the present disclosure is directed to the administration of a reduced rivaroxaban dose (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), in which the reduced rivaroxaban dose is between about 20-99.5% of the recommended dose for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

Thus in some embodiments, the present disclosure is directed to a method of treating a patient in need of a Factor Xa inhibitor, said method comprising the step of administering one or more reduced rivaroxaban dose(s) (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein) of about 0 mg, about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 17.5 mg, about 18 mg, about 19 mg, or less than about 20 mg.

Thus in some embodiments, the present disclosure is directed to the administration of a reduced rivaroxaban dose (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), in which the reduced rivaroxaban dose is between about 0 mg to less than about 20 mg, and all ranges and subranges therebetween as described herein. For example, in some embodiments, the present disclosure is directed to the administration of a reduced rivaroxaban dose (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), in which the reduced rivaroxaban dose is between about 0-10 mg, such as about 0 mg, about 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg.

In some embodiments, the present disclosure is directed to a method of treating a patient in need of a Factor Xa inhibitor, said method comprising the step of administering one or more reduced rivaroxaban dose(s) (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein) of about 10 μg/Kg, 20 μg/Kg, 30 μg/Kg, 40 μg/Kg, 50 μg/Kg, 60 μg/Kg, 70 μg/Kg, 80 μg/Kg, 90 μg/Kg, 100 μg/Kg, 110 μg/Kg, 120 μg/Kg, 130 μg/Kg, 140 μg/Kg, 150 μg/Kg, 160 μg/Kg, 170 μg/Kg, 180 μg/Kg, 190 μg/Kg, 200 μg/Kg, 210 μg/Kg, 220 μg/Kg, 230 μg/Kg, 240 μg/Kg, 250 μg/Kg, 260 μg/Kg, 270 μg/Kg, 280 μg/Kg, 290 μg/Kg, 300 μg/Kg, 310 μg/Kg, 320 μg/Kg, 330 μg/Kg, 340 μg/Kg, 350 μg/Kg, 360 μg/Kg, 370 μg/Kg, 380 μg/Kg, 390 μg/Kg, 400 μg of rivaroxaban per Kilogram of body weight.

Thus in some embodiments, the present disclosure is directed to the administration of a reduced rivaroxaban dose, in which the reduced rivaroxaban dose (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein) is between about 10 μg/kg-300 pg/kg of body weight, inclusive of all ranges and subranges therebetween. For example, in some embodiments, the present disclosure is directed to the administration of a reduced rivaroxaban dose (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), in which the reduced rivaroxaban dose is reduced to between about 100 μg/kg-150 pg/kg of body weight.

In various embodiments, the present disclosure is directed to a method of treating a patient with reduced dose of rivaroxaban relative to the recommended dose of rivaroxaban for an otherwise identical (or the same) patient not concomitantly administered verapamil. Persons having skill in the art will readily recognize that that a clinically effective dose of rivaroxaban for a patient may be dependent on various factors including patient age, sex, body weight, disease progression, overall heath, pathological state, tolerance to the drug, dosing frequency, route of administration, etc. However, the “recommended dose” is the dose recommended in the art, specifically in the package insert for rivaroxaban (incorporated by reference herein), as suitable for a particular patient or patient population based on recognized, clinically relevant physical criteria as established during e.g. clinical trials upon which FDA approval was based. Thus in some embodiments, the present disclosure teaches that an “otherwise identical” patient who is not concomitantly administered verapamil is a patient that has substantially identical physical and biophysical characteristics as the treated patient, other than the administration of verapamil. Thus in some embodiments, an identical patient could be an experimental control patient in studies evaluating the reduced rivaroxaban dosing treatments of the present disclosure.

In the methods of the present disclosure, the rivaroxaban can be administered by any suitable method or mode. For example the compound of the formula (I) can be administered in various forms as described herein, e.g., capsules, tablets, oral solutions or suspensions, dry powders, or parenteral dosage forms such as injectable or IV solutions or suspensions.

In some embodiments, the present disclosure is directed to methods of treating a patient in need of treatment with a Factor Xa inhibitor and who is concomitantly administered verapamil, wherein said method comprises administering more than one dose of rivaroxaban per day. Thus in some embodiments the present disclosure is directed to methods of administering, 1, 2, or 3 doses of rivaroxaban per day. In some embodiments, the present disclosure is directed to administering 2 daily doses of rivaroxaban with food. In various of these embodiments, said multiple doses are reduced doses according to the present disclosure.

In some embodiments, the present disclosure is directed to methods of treating a patient in need of treatment with a Factor Xa inhibitor and who is concomitantly administered verapamil, said method comprising administering a reduced amount of the recommended dose, as described herein, for an otherwise identical (or the same) patient who is not concomitantly administered verapamil, wherein the patient experiences the same or lower C_(max) of rivaroxaban compared to the otherwise identical (or the same) patient who is not concomitantly administered verapamil and is receiving the recommended dose of rivaroxaban. In some embodiments, the present disclosure is directed to administering a reduced rivaroxaban dose (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), wherein the rivaroxaban C_(max) (including steady state C_(max), C_(max ss)) of said patient for the inventive dosing regimen is less than about 500 ng/mL, 495 ng/mL, 490 ng/mL, 485 ng/mL, 480 ng/mL, 475 ng/mL, 470 ng/mL, 465 ng/mL, 460 ng/mL, 455 ng/mL, 450 ng/mL, 445 ng/mL, 440 ng/mL, 435 ng/mL, 430 ng/mL, 425 ng/mL, 420 ng/mL, 415 ng/mL, 410 ng/mL, 405 ng/mL, 400 ng/mL, 395 ng/mL, 390 ng/mL, 385 ng/mL, 380 ng/mL, 375 ng/mL, 370 ng/mL, 365 ng/mL, 360 ng/mL, 355 ng/mL, 350 ng/mL, 345 ng/mL, 340 ng/mL, 335 ng/mL, 330 ng/mL, 325 ng/mL, 320 ng/mL, 317 ng/mL, 315 ng/mL, 310 ng/mL, 305 ng/mL, 300 ng/mL, 295 ng/mL, 290 ng/mL, 285 ng/mL, 280 ng/mL, 275 ng/mL, 270 ng/mL, 265 ng/mL, 260 ng/mL, 255 ng/mL, 250 ng/mL, 245 ng/mL, 240 ng/mL, 235 ng/mL, 230 ng/mL, 225 ng/mL, 220 ng/mL, 215 ng/mL, 210 ng/mL, 205 ng/mL, 200 ng/mL, 195 ng/mL, 190 ng/mL, 185 ng/mL, 180 ng/mL, 175 ng/mL, 170 ng/mL, 165 ng/mL, 160 ng/mL, 158 ng/mL, 155 ng/mL, 150 ng/mL, 145 ng/mL, 140 ng/mL, 135 ng/mL, 130 ng/mL, 125 ng/mL, 120 ng/mL, 115 ng/mL, 110 ng/mL, 105 ng/mL, 100 ng/mL, 95 ng/mL, 90 ng/mL, 85 ng/mL, 80 ng/mL, 75 ng/mL, 70 ng/mL, 65 ng/mL, 60 ng/mL, 55 ng/mL, or about 50 ng/mL, inclusive of all ranges and subranges therebetween.

Thus in some embodiments, the present disclosure is directed to the administration of a reduced rivaroxaban dose (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), in which the reduced rivaroxaban dose produces a rivaroxaban C_(max) (including steady state C_(max), C_(max ss)) between about 158 ng/mL-317 ng/mL, inclusive of all ranges and subranges therebetween. For example, in some embodiments, the present disclosure is directed to the administration of a reduced rivaroxaban dose, in which the reduced rivaroxaban dose produces a rivaroxaban C_(max) (including steady state C_(max), C_(max ss)) of between about 250 ng/mL-300 ng/mL.

In some embodiments, the present disclosure is directed to methods the rivaroxaban dose of patients who are concomitantly administered verapamil is reduced (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), wherein the reduced rivaroxaban dose provides the same or lower AUC of rivaroxaban compared to an otherwise identical (or the same) patient who is not concomitantly administered verapamil and is receiving the recommended rivaroxaban dose. In some embodiments, the present disclosure is directed to the administration of a reduced rivaroxaban dose (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), wherein the rivaroxaban AUC (AUC_(inf) or AUC_(ss)) of said patient is lower than about 200 (μg/L)·h, 225 (μg/L)·h, 250 (μg/L)·h, 275 (μg/L)·h, 300 (μg/L)·h, 325 (μg/L)·h, 350 (μg/L)·h, 375 (μg/L)·h, 400 (μg/L)·h, 425 (μg/L)·h, 450 (μg/L)·h, 475 (μg/L)·h, 500 (μg/L)·h, 525 (μg/L)·h, 550 (μg/L)·h, 575 (μg/L)·h, 600 (μg/L)·h, 625 (μg/L)·h, 650 (μg/L)·h, 675 (μg/L)·h, 700 (μg/L)·h, 725 (μg/L)·h, 750 (μg/L)·h, 775 (μg/L)·h, 800 (μg/L)·h, 825 (μg/L)·h, 850 (μg/L)·h, 875 (μg/L)·h, 900 (μg/L)·h, 925 (μg/L)·h, 950 (μg/L)·h, 975 (μg/L)·h, 1000 (μg/L)·h, 1025 (μg/L)·h, 1050 (μg/L)·h, 1075 (μg/L)·h, 1100 (μg/L)·h, 1125 (μg/L)·h, 1150 (μg/L)·h, 1175 (μg/L)·h, 1200 (μg/L)·h, 1225 (μg/L)·h, 1250 (μg/L)·h, 1275 (μg/L)·h, 1300 (μg/L)·h, 1325 (μg/L)·h, 1350 (μg/L)·h, 1375 (μg/L)·h, 1400 (μg/L)·h, 1425 (μg/L)·h, 1450 (μg/L)·h, 1475 (μg/L)·h, 1500 (μg/L)·h, 1525 (μg/L)·h, 1550 (μg/L)·h, 1575 (μg/L)·h, 1600 (μg/L)·h, 1625 (μg/L)·h, 1650 (μg/L)·h, 1668 (μg/L)·h, 1675 (μg/L)·h, 1700 (μg/L)·h, 1725 (μg/L)·h, 1750 (μg/L)·h, 1775 (μg/L)·h, 1800 (μg/L)·h, 1825 (μg/L)·h, 1850 (μg/L)·h, 1875 (μg/L)·h, 1900 (μg/L)·h, 1925 (μg/L)·h, 1950 (μg/L)·h, 1975 (μg/L)·h, 2000 (μg/L)·h, 2025 (μg/L)·h, 2050 (μg/L)·h, 2075 (μg/L)·h, 2100 (μg/L)·h, 2125 (μg/L)·h, 2150 (μg/L)·h, 2175 (μg/L)·h, 2200 (μg/L)·h, 2225 (μg/L)·h, 2250 (μg/L)·h, 2275 (μg/L)·h, 2300 (μg/L)·h, 2325 (μg/L)·h, 2350 (μg/L)·h, 2375 (μg/L)·h, 2400 (μg/L)·h, 2425 (μg/L)·h, 2450 (μg/L)·h, 2475 (μg/L)·h, 2500 (μg/L)·h, 2525 (μg/L)·h, 2550 (μg/L)·h, 2575 (μg/L)·h, 2600 (μg/L)·h, 2625 (μg/L)·h, 2650 (μg/L)·h, 2675 (μg/L)·h, 2700 (μg/L)·h, 2725 (μg/L)·h, 2750 (μg/L)·h, 2775 (μg/L)·h, 2800 (μg/L)·h, 2825 (μg/L)·h, 2850 (μg/L)·h, 2875 (μg/L)·h, 2900 (μg/L)·h, 2925 (μg/L)·h, 2950 (μg/L)·h, 2975 (μg/L)·h, 3000 (μg/L)·h, 3025 (μg/L)·h, 3050 (μg/L)·h, 3075 (μg/L)·h, 3100 (μg/L)·h, 3125 (μg/L)·h, 3150 (μg/L)·h, 3175 (μg/L)·h, 3200 (μg/L)·h, 3225 (μg/L)·h, 3250 (μg/L)·h, 3275 (μg/L)·h, 3300 (μg/L)·h, 3325 (μg/L)·h, 3350 (μg/L)·h, 3375 (μg/L)·h, 3400 (μg/L)·h, 3425 (μg/L)·h, 3450 (μg/L)·h, 3475 (μg/L)·h, 3500 (μg/L)·h, 3525 (μg/L)·h, 3550 (μg/L)·h, 3575 (μg/L)·h, 3600 (μg/L)·h, 3625 (μg/L)·h, 3650 (μg/L)·h, 3675 (μg/L)·h, 3700 (μg/L)·h, 3725 (μg/L)·h, 3750 (μg/L)·h, 3775 (μg/L)·h, 3792 (μg/L)·h, or about 3800 (μg/L)·h, inclusive of all ranges and subranges there between.

Thus in some embodiments, the present disclosure is directed to the administration of a reduced rivaroxaban dose (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), in which the reduced rivaroxaban dose provides an AUC between about 1668 (μg/L)·h to about 3792 (μg/L)·h, inclusive of all ranges and subranges therebetween. In some embodiments, the present disclosure is directed to the administration of a reduced rivaroxaban dose (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), in which the reduced rivaroxaban dose produces an AUC between about 2000 (μg/L)·h-2400(μg/L)·h.

In some embodiments, the present disclosure is directed to methods of reducing the rivaroxaban dose of patients who are concomitantly administered verapamil (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), wherein the reduced dose causes the patient to maintain the approximately the same maximum prothrombin time compared to an otherwise identical (or the same) patient who is not concomitantly administered verapamil and is receiving the recommended dose of rivaroxaban. Thus in some embodiments, the present disclosure is directed to a reduced rivaroxaban dose (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), wherein the patient's maximum prothrombin time is lower than about 20s, 21s, 22s, 23s, 24s, 25s, 26s, 27s, 28s, 29s, or about 30s.

In some embodiments, the present disclosure is directed to methods of reducing the rivaroxaban dose of patients who are concomitantly administered verapamil (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), wherein the reduced dose of rivaroxaban provides a % risk of major bleeding, for example using the relation shown in FIG. 5, which is less than about 12%, less than about 11%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4.5%, less than about 4%, less than about 3.5%, less than about 3%, less than about 2.5%, less than about 2%, less than about 1.5%, or less than about 1%. In still other embodiments, said patients hereinabove may have normal renal function, or mild, moderate, or severe renal impairment.

In some embodiments, the present disclosure is directed to methods of reducing the rivaroxaban dose of patients with mild renal impairment relative to the recommended dose for an otherwise identical patient having normal renal function, wherein the reduced dose of rivaroxaban provides a % risk of major bleeding, for example using the relation shown in FIG. 5, which is less than about 12%, less than about 11%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4.5%, less than about 4%, less than about 3.5%, less than about 3%, less than about 2.5%, less than about 2%, less than about 1.5%, or less than about 1%.

Thus in some embodiments, the present disclosure is directed to the administration of a reduced rivaroxaban dose (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), in which the reduced rivaroxaban dose causes said patient to exhibit a maximum a prothrombin time between about 20s-30s, inclusive of all ranges and subranges therebetween. For example, in some embodiments, the present disclosure is directed to the administration of a reduced rivaroxaban dose (relative to the recommended dose for an otherwise identical (or the same) patient not concomitantly administered verapamil as described herein), in which the reduced rivaroxaban dose produces a maximum prothrombin time between about 20s-30s.

The present disclosure is also directed to a method of treating a patient in need of treatment with a Factor Xa inhibitor and a calcium channel blocker (such as verapamil), wherein the treatment is to reduce the risk of stroke and systemic embolism in a patient with non valvular atrial fibrillation, the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and for the reduction of the risk of recurrence of DVT and of PE, and for the prophylaxis of DVT which may lead to PE in patients undergoing knee or hip replacement surgery. In some embodiments, the method can include administering a daily dose of about 100, 120, 180, 240 300, 360, or about 480 mg verapamil, including all ranges and subranges therebetween to the patient and administering a dose of rivaroxaban (for example with the evening meal) which is less than the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil. In some embodiments, the patient has mild, moderate, or severe renal impairment.

The present disclosure is also directed to a method of treating a person in need of a calcium channel blocker comprising administering a dose of rivaroxaban (for example with the evening meal) which is less than the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil. The present disclosure is also directed to a method of treating essential hypertension in a patient. In some embodiments, the method can include administering a daily dose of about 100, 120, 180, 240, about 360, or about 480 mg verapamil, including all ranges and subranges therebetween to the patient, and administering a dose of rivaroxaban (for example with the evening meal) which is less than the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil. In some embodiments, the patient can have mild, moderate, or severe renal impairment and is in need of anticoagulant therapy.

The present disclosure also directs to a method of treating a patient in need of treatment with a factor Xa inhibitor and a calcium channel blocker (such as verapamil), wherein the treatment is to reduce the risk of stroke and systemic embolism in a patient with non valvular atrial fibrillation, the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and for the reduction of the risk of recurrence of DVT and of PE, and for the prophylaxis of DVT which may lead to PE in patients undergoing knee or hip replacement surgery. In some embodiments, the method can include administering a daily dose of a calcium channel blocker to the patient and administering a dose of rivaroxaban (for example with the evening meal) which is less than the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil. In some embodiments, the patient has mild, moderate, or severe renal impairment.

The present disclosure is also directed to a method of treating essential hypertension in a patient. In some embodiments, the method can include administering a calcium channel blocker to the patient, and administering a dose of rivaroxaban (for example with the evening meal) which is less than the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil. In some embodiments, the patient can have mild, moderate, or severe renal impairment and is in need of anticoagulant therapy.

In some embodiments, the patient has a CL_(Cr) of greater than or equal to about 90 mL/min, greater than or equal to about 80 mL/min, about 50-79 mL/min, about 60-89 mL/min, about 30-49 mL/min, about 30-59 mL/min, less than about 30 mL/min, about 15-29 mL/min, or less than about 15 mL/min, including all ranges and all subranges therebetween. In some embodiments, the dose of rivaroxaban is less than the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil, and about 0%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99.5% and all ranges and subranges therebetween of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

In some embodiments, the patient has a CL_(Cr) of greater than or equal to about 90 mL/min, greater than or equal to about 80 mL/min, about 50-79 mL/min, about 60-89 mL/min, about 30-49 mL/min, about 30-59 mL/min, less than about 30 mL/min, about 15-29 mL/min, or less than about 15 mL/min, including all ranges and all subranges therebetween and the dose of rivaroxaban is less than: about 19.9 mg, about 19 mg, about 18 mg, about 17.5 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12.5 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2.5 mg, about 2 mg, about 1 mg, or about 0 mg, including all ranges and subranges therebetween. In some embodiments, the dose of rivaroxaban is less than the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil, and about 0 mg, at least about 1 mg, at least about 2 mg, at least about 2.5 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 7.5 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 12.5 mg, at least about 13 mg, at least about 14 mg, or less than about 15 mg, including all ranges and subranges therebetween. In some embodiments, the daily dose of verapamil is 100 mg. In some embodiments, the daily dose of verapamil is 120 mg. In some embodiments, the daily dose of verapamil is 180 mg. In some embodiments, the daily dose of verapamil is 240 mg. In some embodiments, the daily dose of verapamil is 360 mg. In some embodiments, the daily dose of verapamil is 480 mg.

The present disclosure is also directed to a method of treating coronary artery disease in a patient. In some embodiments, the present disclosure is directed to a method of treating peripheral artery disease in a patient. In some embodiments, the present disclosure is directed to a method of treating atrial fibrillation. In some embodiments, the present disclosure is directed to a method of treating deep vein thrombosis. In some embodiments, the present disclosure is directed to a method of treating patients undergoing major orthopedic surgery. In some embodiments, the present disclosure is directed to a method of deep vein thrombosis prophylaxis. In some embodiments, the present disclosure is directed to a method of deep vein thrombosis prophylaxis after abdominal surgery. In some embodiments, the present disclosure is directed to a method of deep vein thrombosis prophylaxis after hip replacement surgery. In some embodiments, the present disclosure is directed to a method of deep vein thrombosis prophylaxis after knee replacement surgery. In some embodiments, the present disclosure is directed to a method of treating a deep vein thrombosis recurring event. In some embodiments, the present disclosure is directed to a method of treating a heart attack patient. In some embodiments, the present disclosure is directed to a method of prevention of thromboembolism in atrial fibrillation. In some embodiments, the present disclosure is directed to a method of treating pulmonary embolism. In some embodiments, the present disclosure is directed to a method of treating a pulmonary embolism recurring event. In some embodiments, the present disclosure is directed to thromboembolic stroke prophylaxis. In some embodiments, the present disclosure is directed to a method of treating venous thromboembolism. In some embodiments, the present disclosure is directed to a method of prevention of ischemic stroke. In some embodiments, the present disclosure is directed to a method of treating recurring myocardial infarction. In some embodiments, the present disclosure is directed to a method of treating antiphospholipid antibody syndrome. In some embodiments, the present disclosure is directed to a method of treating sickle cell disease. In some embodiments, the present disclosure is directed to a method of prevention and treatment of venous thromboembolism in cancer patients. In some embodiments, the present disclosure is directed to a method of treating cancer associated thrombosis. In some embodiments, the present disclosure is directed to a method of treating cancer patients with central line associated clots in the upper extremity. In some embodiments, the present disclosure is directed to a method of reducing post-discharge venous thromboembolism risk in medically ill patients. In some embodiments, the present disclosure is directed to a method of treating young children with venous thrombosis (6 months-5 years). In some embodiments, the present disclosure is directed to a method of treating arterial or venous thrombosis in children from birth to less than 6 months. In some embodiments, the present disclosure is directed to a method of treating thrombophylaxis in pediatric patients 2 to 8 years of age after the fontan procedure. In some embodiments, the present disclosure is directed to a method of treating valvular heart disease and atrial fibrillation. In some embodiments, the present disclosure is directed to a method of treating patients with atrial fibrillation with bioprosthetic mitral valves. In some embodiments, the present disclosure is directed to a method of treating symptomatic isolated distal deep vein thrombosis. In some embodiments, the present disclosure is directed to a method of treating superficial vein thrombosis. In some embodiments, the present disclosure is directed to a method of prevention of thrombosis after replacement of the aortic valve with a biological valve prosthesis. In some embodiments, the present disclosure is directed to a method of prevention of recurrence of stent thrombosis and cardiovascular events in patients with atrial fibrillation complicated with stable coronary artery disease. In some embodiments, the present disclosure is directed to a method of treating splanchnic vein thrombosis. In some embodiments, the present disclosure is directed to a method of prevention of recurrent thrombosis in patients with chronic portal vein thrombosis. In some embodiments, the present disclosure is directed to a method of prevention of recurrent symptomatic venous thromboembolism in patients with symptomatic deep vein thrombosis or pulmonary embolism. In some embodiments, the present disclosure is directed to a method of treating acute ischemic stroke with atrial fibrillation. In some embodiments, the present disclosure is directed to a method of venous thromboembolism prophylaxis in patients undergoing non-major orthopedic surgery. In some embodiments, the present disclosure is directed to a method of reducing the risk of major thrombotic vascular events in subjects with peripheral artery disease undergoing peripheral revascularization procedures of the lower extremities. In some embodiments, the present disclosure is directed to a method of prevention of cardiovascular events in patients with nonvalvular atrial fibrillation scheduled for cardioversion. In some embodiments, the present disclosure is directed to a method of reducing the risk of death, myocardial infarction, or stroke in participants with heart failure and coronary artery disease following an episode of decompensated heart failure. In some embodiments, the present disclosure is directed to a method of preventing major cardiovascular events in coronary or peripheral artery disease. In some embodiments, the present disclosure is directed to a method of reducing the risk of cardiovascular death, myocardial infarction, or stroke in patients with recent acute coronary syndrome. In some embodiments, the present disclosure is directed to a method of prevention of the composite of stroke or systemic embolism in patients with rheumatic valvular heart disease (RVHD) with atrial fibrillation or flutter who are unsuitable for vitamin K antagonist therapy, or in patients with RVHD without AF or flutter with at least one of the following: left atrial enlargement ≥5.5 cm, left atrial spontaneous echo contrast, left atrial thrombus, or frequent ectopic atrial activity (>1000/24 hours) on Holter ECG. In some embodiments, the present disclosure is directed to a method of prevention of restenosis after infrainguinal percutaneous transluminal angioplasty for critical limb ischemia. In some embodiments, the present disclosure is directed to a method of decreasing the risk of cardiovascular disease, myocardial infarction, revascularization, ischemic stroke, and systemic embolism.

In some embodiments, the present disclosure is directed to treatment of a patient with a medical condition requiring treatment with a calcium channel blocker such as verapamil (in conjunction with a Factor Xa inhibitor), including management of essential hypertension. In some embodiments, the present disclosure is directed to treatment of hypertension In some embodiments, the present disclosure is directed to treatment of pulmonary hypertension. In some embodiments, the present disclosure is directed to prevention and treatment of recurrent and paroxysmal supraventricular tachycardia. In some embodiments, the present disclosure is directed to management of supraventricular tachycardia. In some embodiments, the present disclosure is directed to treatment of atrial tachycardia. In some embodiments, the present disclosure is directed to treatment of junctional tachycardia. In some embodiments, the present disclosure is directed to treatment of cerebral vasospasm. In some embodiments, the present disclosure is directed to treatment of hypertrophic cardiomyopathy. In some embodiments, the present disclosure is directed to treatment of chronic stable angina pectoris. In some embodiments, the present disclosure is directed to treatment of unstable angina pectoris. In some embodiments, the present disclosure is directed to management of Prinzmetal variant angina. In some embodiments, the present disclosure is directed to ventricular rate control in atrial fibrillation/flutter. In some embodiments, the present disclosure is directed to prevention of cluster headache. In some embodiments, the present disclosure is directed to prevention of migraine. In some embodiments, the present disclosure is directed to prevention of myocardial infarction in patients with preserved left ventricular function. In some embodiments, the present disclosure is directed to management of manic manifestations of bipolar disorder. In some embodiments, the present disclosure is directed to treatment of Raynaud's disease. In some embodiments, the present disclosure is directed to treatment of coronary artery disease. In some embodiments, the present disclosure is directed to treatment of subarachnoid hemorrhage. In some embodiments, the present disclosure is directed to treatment of Dravet Syndrome. In some embodiments, the present disclosure is directed to beta cell survival therapy in Type I diabetes. In some embodiments, the present disclosure is directed to treatment of vestibular migraine. In some embodiments, the present disclosure is directed to treatment of chronic subjective dizziness. In some embodiments, the present disclosure is directed to treatment of erectile dysfunction. In some embodiments, the present disclosure is directed to prevention of keloid recurrence. In some embodiments, the present disclosure is directed to treatment of refractory epilepsy. In some embodiments, the present disclosure is directed to treatment of refractory meningioma. In some embodiments, the present disclosure is directed to treatment of chronic heart failure secondary to non-ischemic cardiomyopathy. In some embodiments, the present disclosure is directed to treatment of relapsed or refractory Hodgkin lymphoma. In some embodiments, the present disclosure is directed to treatment of Marfan Syndrome. In some embodiments, the present disclosure is directed to treatment of treatment-resistant mania. In some embodiments, the present disclosure is directed to prevention of kidney disease in diabetic patients. In some embodiments, the present disclosure is directed to treatment of Metabolic Syndrome. In some embodiments, the present disclosure is directed to treatment of hypoglycemia following gastric bypass.

In some embodiments, the method can include administering rivaroxaban only to the patient. In some embodiments, the administering can be once daily. In some embodiments, the single dose of rivaroxaban is about 19.9 mg, about 19 mg, about 18 mg, about 17.5 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12.5 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2.5 mg, about 2 mg, about 1 mg, about 0 mg, or any ranges and subranges therebetween. In some embodiments, the daily dose of rivaroxaban is 0 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg. In some embodiments, the method can include administering rivaroxaban with aspirin daily. In some embodiments, the frequency of administering rivaroxaban is twice daily. In some embodiments, the frequency of administering aspirin is once daily.

In some embodiments, when aspirin is coadministered with rivaroxaban as described herein, the single dose of aspirin can be about 150 mg, about 140 mg, about 130 mg, about 120 mg, about 110 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, or any ranges and subranges therebetween. In some embodiments, the daily dose of aspirin is 100 mg. In some embodiments, the method can include administering aspirin only to the patient. In some embodiments, the administering can be once daily. In some embodiments, the daily dose of aspirin can be 150 mg, about 140 mg, about 130 mg, about 120 mg, about 110 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, or any ranges and subranges therebetween. In some embodiments, the daily dose of aspirin is 100 mg.

In some embodiments, the methods described herein can prevent major adverse cardiac events. In some embodiments, the adverse cardiac events can include, but are not limited to cardiovascular death, myocardial infarction and stroke. In some embodiments, the methods can be used to prevent stroke and systemic embolism in adult patients. In some embodiments, the patients have non-valvular atrial fibrillation (AF) with one or more risk factors. In some embodiments, the methods can be used to prevent or treat pulmonary embolism (PE) in adults. In some embodiments, the methods can be used to prevent or treat deep vein thrombosis (DVT) in adults. In some embodiments, the methods can be used to concurrently prevent or treat recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults. In some embodiments, the methods can be used to prevent or treat venous thromboembolism (VTE) in adult patients. In other embodiments, the adult patients undergo elective hip replacement surgery.

In some embodiments, the methods can be used to prevent or treat venous thromboembolism (VTE) in adult patients. In other embodiments, the adult patients undergo elective knee replacement surgery. In some embodiments, the methods can be used to prevent or treat atherothrombotic events. In some embodiments, the atherothrombotic events can include but are not limited to cardiovascular death, myocardial infarction or stroke. In some embodiments, the prevention or treatment can be after an Acute Coronary Syndrome in adult patients. In some embodiments, the adult patients have elevated cardiac biomarkers. In other embodiments, the adult patients have no prior stroke or transient ischaemic attack (TIA) when co-administered with acetylsalicylic acid (ASA) alone. In some embodiments, the adult patients have no prior stroke or transient ischaemic attack (TIA) when co-administered with acetylsalicylic acid (ASA) plus clopidogrel. In some embodiments, the adult patients have no prior stroke or transient ischaemic attack (TIA) when co-administered with acetylsalicylic acid (ASA) plus or ticlopidine.

The following are particular but not limiting embodiments of the present disclosure:

1. A method of treating a patient in need of treatment with a Factor Xa inhibitor and who is concomitantly administered verapamil, comprising administering a dose of rivaroxaban which is about 0-99.5% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

2. The method of embodiment 1, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is about 50% of the dose recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil.

3. The method of embodiment 1, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is about 75% of the dose recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil.

4 The method of embodiment 1, wherein the patient who is concomitantly administered rivaroxaban and verapamil is not renally impaired.

5. The method of embodiment 1, wherein the patient who is concomitantly administered rivaroxaban and verapamil is mildly renally impaired.

6. The method of embodiment 1, wherein the patient who is concomitantly administered rivaroxaban and verapamil is moderately renally impaired.

7. The method of embodiment 1, wherein the patient who is concomitantly administered rivaroxaban and verapamil is severely renally impaired.

8. The method of embodiment 1, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 80 mL/min.

9. The method of embodiment 1, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 90 mL/min.

10. The method of embodiment 1, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 50-79 mL/min.

11 The method of embodiment 1, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 60-89 mL/min.

12. The method of embodiment 1, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-49 mL/min.

13 The method of embodiment 1, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-59 mL/min.

14. The method of embodiment 1, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 30 mL/min.

15. The method of embodiment 1, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 15-29 mL/min.

16. The method of embodiment 1, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 15 mL/min.

17. The method of embodiment 1, wherein 3 hours after administration of rivaroxaban to the patient who is concomitantly administered verapamil, the prothrombin time of said patient ranges from about 20-30 seconds.

18. The method of embodiment 1, wherein the plasma concentration of rivaroxaban 1 hour after administration of rivaroxaban to the patient who is concomitantly administered verapamil is no more than about 317 ng/mL.

19. The method of embodiment 1, wherein the AUC of rivaroxaban for the patient concomitantly administered verapamil is in the range of about 1668 (μg/L)·h-3792 (μg/L)·h.

20. The method of embodiment 1, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is about 0 mg to about 19.9 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

21. The method of embodiment 1, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 10 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

22. The method of embodiment 1, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 15 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

23. The method of embodiment 1, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 10 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 15 mg.

24. The method of embodiment 8, wherein 3 hours after said coadministration of rivaroxaban to the patient who is concomitantly administered verapamil, the prothrombin time of said patient ranges from about 20-30 seconds.

25. The method of embodiment 8, wherein the plasma concentration of rivaroxaban 1 hour after administration of rivaroxaban to the patient who is concomitantly administered verapamil is no more than about 317 ng/mL.

26. The method of embodiment 8, wherein the daily dose of verapamil is 100 to 480 mg.

27. The method of embodiment 9, wherein the daily dose of verapamil is 100 to 480 mg.

28. The method of embodiment 10, wherein the daily dose of verapamil is 100 to 480 mg.

29. The method of embodiment 11, wherein the daily dose of verapamil is 100 to 480 mg.

30. The method of embodiment 1, wherein the verapamil is administered intravenously or orally.

31. The method of embodiment 24, wherein the intravenous verapamil has a pH of about 4.1-6.0.

32. The method of embodiment 1, wherein the verapamil is coadministered with trandolapril.

33. The method of embodiment 1, wherein the verapamil is in the form of a hydrochloride salt.

34. The method of embodiment 1, wherein the daily verapamil dose is greater than about 40 mg.

35. The method of embodiment 1, wherein the patient is diabetic.

36. The method of embodiment 1, wherein the patient has had an episode of atrial fibrillation within the last six months of said administering.

37. The method of embodiment 1, further comprising discontinuing coadmininstration of rivaroxaban and verapamil if a change in rivaroxaban exposure (as measured by AUC) is observed to be greater than 150% or an increase in the prothrombin time is observed to be greater than 45%.

38. The method of embodiment 1, further comprising after initially administering a dose of rivaroxaban which is about 0-99.5% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil, one or more subsequent doses of rivaroxaban which are the dose or doses recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

39. A method of reducing side effects in a patient concomitantly administered verapamil and rivaroxaban, comprising administering a dose of rivaroxaban which is about 0-99.5% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

40. The method of embodiment 39, wherein the dose of rivaroxaban administered to the patient is 0-19.9 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

41. The method of embodiment 39, wherein the dose of rivaroxaban administered to the patient is 10 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

42. The method of embodiment 39, wherein the dose of rivaroxaban administered to the patient is 15 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

43. The method of embodiment 39, wherein the dose of rivaroxaban administered to the patient is 10 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 15 mg.

44. The method of embodiment 40, wherein the daily dose of verapamil is 100 to 480 mg.

45. The method of embodiment 41, wherein the daily dose of verapamil is 100 to 480 mg.

46. The method of embodiment 42, wherein the daily dose of verapamil is 100 to 480 mg.

47. The method of embodiment 43, wherein the daily dose of verapamil is 100 to 480 mg.

48. The method of embodiment 39, wherein the verapamil is administered intravenously or orally.

49. The method of embodiment 48, wherein the intravenous verapamil has a pH of about 4.1-6.0.

50. The method of embodiment 39, wherein the verapamil is coadministered with trandolapril.

51. The method of embodiment 39, wherein the verapamil is in the form of a hydrochloride salt.

52. The method of embodiment 39, wherein the daily verapamil dose is greater than about 40 mg.

53. The method of embodiment 39, wherein the patient is diabetic.

54. The method of embodiment 39, wherein the patient has had an episode of atrial fibrillation within the last six months of said administering.

55. The method of embodiment 39, further comprising discontinuing coadministration of rivaroxaban and verapamil if a change in rivaroxaban exposure (as measured by AUC) is observed to be greater than 150% or an increase in the prothrombin time is observed to be greater than 45%.

56. The method of embodiment 39, further comprising after initially administering a dose of rivaroxaban which is about 0-99.5% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil, one or more subsequent doses of rivaroxaban which are the dose or doses recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

57. A method of managing the risk of a rivaroxaban/verapamil interaction in a patient in need of treatment with a Factor Xa inhibitor and who is concomitantly administered verapamil, comprising administering a dose of rivaroxaban which is about 0-99.5% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

58. The method of embodiment 57, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is about 50% of the dose recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil.

59. The method of embodiment 57, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is about 75% of the dose recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil.

60. The method of embodiment 57, wherein the patient who is concomitantly administered rivaroxaban and verapamil is not renally impaired.

61. The method of embodiment 57, wherein the patient who is concomitantly administered rivaroxaban and verapamil is mildly renally impaired.

62. The method of embodiment 57, wherein the patient who is concomitantly administered rivaroxaban and verapamil is moderately renally impaired.

63. The method of embodiment 57, wherein the patient who is concomitantly administered rivaroxaban and verapamil is severely renally impaired.

64. The method of embodiment 57, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 80 mL/min.

65. The method of embodiment 57, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 90 mL/min.

66. The method of embodiment 57, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 50-79 mL/min.

67. The method of embodiment 57, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 60-89 mL/min.

68. The method of embodiment 57, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-49 mL/min.

69. The method of embodiment 57, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-59 mL/min.

70. The method of embodiment 57, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 30 mL/min.

71. The method of embodiment 57, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 15-29 mL/min.

72. The method of embodiment 57, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 15 mL/min.

73. The method of embodiment 57, wherein 3 hours after administration of rivaroxaban to the patient who is concomitantly administered verapamil, the prothrombin time of said patient ranges from about 20-30 seconds.

74. The method of embodiment 57, wherein the plasma concentration of rivaroxaban 1 hour after administration of rivaroxaban to the patient who is concomitantly administered verapamil is no more than about 317 ng/mL.

75. The method of embodiment 57, wherein the AUC of rivaroxaban for the patient concomitantly administered verapamil is in the range of about 1668 (μg/L)·h-3792 (μg/L)·h.

76. The method of embodiment 57, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 0-19.9 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

77. The method of embodiment 57, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 10 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

78. The method of embodiment 57, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 15 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

79. The method of embodiment 57, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 10 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 15 mg.

80. The method of embodiment 76, wherein the patient who is concomitantly administered rivaroxaban and verapamil is not renally impaired.

81. The method of embodiment 76, wherein the patient who is concomitantly administered rivaroxaban and verapamil is mildly renally impaired.

82. The method of embodiment 76, wherein the patient who is concomitantly administered rivaroxaban and verapamil is moderately renally impaired.

83. The method of embodiment 76, wherein the patient who is concomitantly administered rivaroxaban and verapamil is severely renally impaired.

84. The method of embodiment 76, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 80 mL/min.

85. The method of embodiment 76, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 90 mL/min.

86. The method of embodiment 76, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 50-79 mL/min.

87. The method of embodiment 76, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 60-89 mL/min.

88. The method of embodiment 76, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-49 mL/min.

89. The method of embodiment 76, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-59 mL/min.

90. The method of embodiment 76, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 30 mL/min.

91. The method of embodiment 76, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 15-29 mL/min.

92. The method of embodiment 76, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 15 mL/min.

93. The method of embodiment 76, wherein 3 hours after said coadministration of rivaroxaban to the patient who is concomitantly administered verapamil, the prothrombin time of said patient ranges from about 20-30 seconds.

94. The method of embodiment 76, wherein the plasma concentration of rivaroxaban 1 hour after administration of rivaroxaban to the patient who is concomitantly administered verapamil is no more than about 317 ng/mL.

95. The method of embodiment 76, wherein the daily dose of verapamil is 100 to 480 mg.

96. The method of embodiment 77, wherein the daily dose of verapamil is 100 to 480 mg.

97. The method of embodiment 78, wherein the daily dose of verapamil is 100 to 480 mg.

98. The method of embodiment 79, wherein the daily dose of verapamil is 100 to 480 mg.

99. The method of embodiment 57, wherein the verapamil is administered intravenously or orally.

100. The method of embodiment 99, wherein the intravenous verapamil has a pH of about 4.1-6.0.

101. The method of embodiment 57, wherein the verapamil is coadministered with trandolapril.

102. The method of embodiment 57, wherein the verapamil is in the form of a hydrochloride salt.

103. The method of embodiment 57, wherein the verapamil daily dose is greater than about 40 mg.

104. The method of embodiment 57, wherein the patient is diabetic.

105. The method of embodiment 57, wherein the patient has had an episode of atrial fibrillation within the last six months of said administering.

106. The method of embodiment 57, further comprising discontinuing coadministration of rivaroxaban and verapamil if a change in rivaroxaban exposure (as measured by AUC) is observed to be greater than 150% or an increase in the prothrombin time is observed to be greater than 45%.

107. The method of embodiment 57, further comprising after initially administering a dose of rivaroxaban which is about 0-99.5% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil, one or more subsequent doses of rivaroxaban which are the dose or doses recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

108. A method of reducing the frequency of excessive bleeding in a patient in need of treatment with a Factor Xa inhibitor and who is concomitantly administered verapamil, comprising administering a dose of rivaroxaban which is about 0-99.5% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

109. The method of embodiment 108, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is about 50% of the dose recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil.

110. The method of embodiment 108, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is about 75% of the dose recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil.

111. The method of embodiment 108, wherein the patient who is concomitantly administered rivaroxaban and verapamil is not renally impaired.

112. The method of embodiment 108, wherein the patient who is concomitantly administered rivaroxaban and verapamil is mildly renally impaired.

113. The method of embodiment 108, wherein the patient who is concomitantly administered rivaroxaban and verapamil is moderately renally impaired.

114. The method of embodiment 108, wherein the patient who is concomitantly administered rivaroxaban and verapamil is severely renally impaired.

115. The method of embodiment 108, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 80 mL/min.

116. The method of embodiment 108, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 90 mL/min.

117. The method of embodiment 108, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 50-79 mL/min.

118. The method of embodiment 108, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 60-89 mL/min.

119. The method of embodiment 108, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-49 mL/min.

120. The method of embodiment 108, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-59 mL/min.

121. The method of embodiment 108, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 30 mL/min.

122. The method of embodiment 108, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 15-29 mL/min.

123. The method of embodiment 108, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 15 mL/min.

124. The method of embodiment 180, wherein 3 hours after administration of rivaroxaban to the patient who is concomitantly administered verapamil, the prothrombin time of said patient ranges from about 20-30 seconds.

125. The method of embodiment 108, wherein the plasma concentration of rivaroxaban 1 hour after administration of rivaroxaban to the patient who is concomitantly administered verapamil is no more than about 317 ng/mL.

126. The method of embodiment 108, wherein the AUC of rivaroxaban for the patient concomitantly administered verapamil is in the range of about 1668 (μg/L)·h-3792 (μg/L)·h.

127. The method of embodiment 108, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 0-19.9 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

128. The method of embodiment 108, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 10 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

129. The method of embodiment 108, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 15 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

130. The method of embodiment 108, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 10 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 15 mg.

131. The method of embodiment 127, wherein the patient who is concomitantly administered rivaroxaban and verapamil is not renally impaired.

132. The method of embodiment 127, wherein the patient who is concomitantly administered rivaroxaban and verapamil is mildly renally impaired.

133. The method of embodiment 127, wherein the patient who is concomitantly administered rivaroxaban and verapamil is moderately renally impaired.

134. The method of embodiment 127, wherein the patient who is concomitantly administered rivaroxaban and verapamil is severely renally impaired.

135. The method of embodiment 127, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 80 mL/min.

136. The method of embodiment 127, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 90 mL/min.

137. The method of embodiment 127, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 50-79 mL/min.

138. The method of embodiment 127, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 60-89 mL/min.

139. The method of embodiment 127, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-49 mL/min.

140. The method of embodiment 127, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-59 mL/min.

141. The method of embodiment 127, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 30 mL/min.

142. The method of embodiment 127, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 15-29 mL/min.

143. The method of embodiment 127, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 15 mL/min.

144. The method of embodiment 127, wherein 3 hours after said coadministration of rivaroxaban to the patient who is concomitantly administered verapamil, the prothrombin time of said patient ranges from about 20-30 seconds.

145. The method of embodiment 127, wherein the plasma concentration of rivaroxaban 1 hour after administration of rivaroxaban to the patient who is concomitantly administered verapamil is no more than about 317 ng/mL.

146. The method of embodiment 127, wherein the daily dose of verapamil is 100 to 480 mg.

147. The method of embodiment 128, wherein the daily dose of verapamil is 100 to 480 mg.

148. The method of embodiment 129, wherein the daily dose of verapamil is 100 to 480 mg.

149. The method of embodiment 130, wherein the daily dose of verapamil is 100 to 480 mg.

150. The method of embodiment 90, wherein the verapamil is administered intravenously or orally.

151. The method of embodiment 150, wherein the intravenous verapamil has a pH of about 4.1-6.0.

152. The method of embodiment 108, wherein the verapamil is coadministered with trandolapril.

153. The method of embodiment 108, wherein the verapamil is in the form of a hydrochloride salt.

154. The method of embodiment 108, wherein the verapamil daily dose is greater than about 40 mg.

155. The method of embodiment 108, wherein the patient is diabetic.

156. The method of embodiment 108, wherein the patient has had an episode of atrial fibrillation within the last six months of said administering.

157. The method of embodiment 108, further comprising discontinuing coadmininstration of rivaroxaban and verapamil if a change in rivaroxaban exposure (as measured by AUC) is observed to be greater than 150% or an increase in the prothrombin time is observed to be greater than 45%.

158. The method of embodiment 108, further comprising after initially administering a dose of rivaroxaban which is about 0-99.5% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil, one or more subsequent doses of rivaroxaban which are the dose or doses recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

159. A method of reducing the frequency of clot formation in a patient in need of treatment with a Factor Xa inhibitor and who is concomitantly administered verapamil, comprising administering a dose of rivaroxaban which is about 0-99.5% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

160. The method of embodiment 159, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is about 50% of the dose recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil.

161. The method of embodiment 159, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is about 75% of the dose recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil.

162. The method of embodiment 159, wherein the patient who is concomitantly administered rivaroxaban and verapamil is not renally impaired.

163. The method of embodiment 159, wherein the patient who is concomitantly administered rivaroxaban and verapamil is mildly renally impaired.

164. The method of embodiment 159, wherein the patient who is concomitantly administered rivaroxaban and verapamil is moderately renally impaired.

165. The method of embodiment 159, wherein the patient who is concomitantly administered rivaroxaban and verapamil is severely renally impaired.

166. The method of embodiment 159, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 80 mL/min.

167. The method of embodiment 159, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 90 mL/min.

168. The method of embodiment 159, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 50-79 mL/min.

169. The method of embodiment 159, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 60-89 mL/min.

170. The method of embodiment 159, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-49 mL/min.

171. The method of embodiment 159, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-59 mL/min.

172. The method of embodiment 159, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 30 mL/min.

173. The method of embodiment 159, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 15-29 mL/min.

174. The method of embodiment 159, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 15 mL/min.

175. The method of embodiment 159, wherein 3 hours after administration of rivaroxaban to the patient who is concomitantly administered verapamil, the prothrombin time of said patient ranges from about 20-30 seconds.

176. The method of embodiment 159, wherein the plasma concentration of rivaroxaban 1 hour after administration of rivaroxaban to the patient who is concomitantly administered verapamil is no more than about 317 ng/mL.

177. The method of embodiment 159, wherein the AUC of rivaroxaban for the patient concomitantly administered verapamil is in the range of about 1668 (μg/L)·h-3792 (μg/L)·h.

178. The method of embodiment 159, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 0-19.9 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

179. The method of embodiment 159, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 10 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

180. The method of embodiment 159, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 15 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

181. The method of embodiment 159, wherein the dose of rivaroxaban administered to the patient who is concomitantly administered verapamil is 10 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 15 mg.

182. The method of embodiment 178, wherein the patient who is concomitantly administered rivaroxaban and verapamil is not renally impaired.

183. The method of embodiment 178, wherein the patient who is concomitantly administered rivaroxaban and verapamil is mildly renally impaired.

184. The method of embodiment 178, wherein the patient who is concomitantly administered rivaroxaban and verapamil is moderately renally impaired.

185. The method of embodiment 178, wherein the patient who is concomitantly administered rivaroxaban and verapamil is severely renally impaired.

186. The method of embodiment 178, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 80 mL/min.

187. The method of embodiment 178, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 90 mL/min.

188. The method of embodiment 178, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 50-79 mL/min.

189. The method of embodiment 178, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 60-89 mL/min.

190. The method of embodiment 178, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-49 mL/min.

191. The method of embodiment 178, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-59 mL/min.

192. The method of embodiment 178, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 30 mL/min.

193. The method of embodiment 178, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 15-29 mL/min.

194. The method of embodiment 178, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 15 mL/min.

195. The method of embodiment 178, wherein 3 hours after said coadministration of rivaroxaban to the patient who is concomitantly administered verapamil, the prothrombin time of said patient ranges from about 20-30 seconds.

196. The method of embodiment 178, wherein the plasma concentration of rivaroxaban 1 hour after administration of rivaroxaban to the patient who is concomitantly administered verapamil is no more than about 317 ng/mL.

197. The method of embodiment 178, wherein the daily dose of verapamil is 100 to 480 mg.

198. The method of embodiment 179, wherein the daily dose of verapamil is 100 to 480 mg.

199. The method of embodiment 180, wherein the daily dose of verapamil is 100 to 480 mg.

200. The method of embodiment 181, wherein the daily dose of verapamil is 100 to 480 mg.

201. The method of embodiment 159, wherein the verapamil is administered intravenously or orally.

202. The method of embodiment 181, wherein the intravenous verapamil has a pH of about 4.1-6.0.

203. The method of embodiment 159, wherein the verapamil is coadministered with trandolapril.

204. The method of embodiment 159, wherein the verapamil is in the form of a hydrochloride salt.

205. The method of embodiment 159, wherein the daily verapamil dose is greater than about 40 mg.

206. The method of embodiment 159, wherein the patient is diabetic.

207. The method of embodiment 159, wherein the patient has had an episode of atrial fibrillation within the last six months of said administering.

208. The method of embodiment 159, further comprising discontinuing coadministration of rivaroxaban and verapamil if a change in rivaroxaban exposure (as measured by AUC) is observed to be greater than 150% or an increase in the prothrombin time is observed to be greater than 45%.

209. The method of embodiment 159, further comprising after initially administering a dose of rivaroxaban which is about 50-99.5% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil, one or more subsequent doses of rivaroxaban which are the dose or doses recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

210. A package comprising a packaging material, one or more unit doses of rivaroxaban, and a label or package insert combined therein, wherein the package insert comprises a printed statement informing a prospective user that rivaroxaban is a Factor Xa inhibitor indicated for one or more of the conditions disclosed herein;

-   -   wherein when the rivaroxaban is coadministered with verapamil,         the dose of rivaroxaban to be administered is about 0-99.5% of         the dose recommended for an otherwise identical (or the same)         patient who is not concomitantly administered verapamil.

211. A method of treating a condition with a Factor Xa inhibitor, and a calcium channel blocker, comprising:

-   -   (a) administering about 100 to about 480 mg verapamil daily to         the patient; and     -   (b) administering a dose of rivaroxaban with the evening meal         which is less than the dose recommended for an otherwise         identical (or the same) patient who is not concomitantly         administered verapamil;     -   wherein said condition is selected from the group consisting of         atrial fibrillation; deep vein thrombosis; patients undergoing         major orthopedic surgery; deep vein thrombosis prophylaxis, deep         vein thrombosis prophylaxis after abdominal surgery; deep vein         thrombosis prophylaxis after hip replacement surgery; deep vein         thrombosis prophylaxis after knee replacement surgery; deep vein         thrombosis recurring event; heart attack; prevention of         thromboembolism in atrial fibrillation; pulmonary embolism;         pulmonary embolism recurring event; thromboembolic stroke         prophylaxis; venous thromboembolism; prevention of ischemic         stroke; recurring myocardial infarction; antiphospholipid         antibody syndrome; sickle cell disease; prevention and treatment         of venous thromboembolism in cancer patients; cancer associated         thrombosis; cancer patients with central line associated clots         in the upper extremity; reducing post-discharge venous         thromboembolism risk in medically ill patients; treating young         children with venous thrombosis (6 months-5 years); treatment of         arterial or venous thrombosis in children from birth to less         than 6 months; thrombophylaxis in pediatric patients 2 to 8         years of age after the fontan procedure; valvular heart disease         and atrial fibrillation; patients with atrial fibrillation with         bioprosthetic mitral valves; treatment of symptomatic isolated         distal deep vein thrombosis; superficial vein thrombosis;         prevention of thrombosis after replacement of the aortic valve         with a biological valve prosthesis; prevention of recurrence of         stent thrombosis and cardiovascular events in patients with         atrial fibrillation complicated with stable coronary artery         disease; treatment of splanchnic vein thrombosis; prevention of         recurrent thrombosis in patients with chronic portal vein         thrombosis; prevention of recurrent symptomatic venous         thromboembolism in patients with symptomatic deep vein         thrombosis or pulmonary embolism; acute ischemic stroke with         atrial fibrillation; venous thromboembolism prophylaxis in         patients undergoing non-major orthopedic surgery; reducing the         risk of major thrombotic vascular events in subjects with         peripheral artery disease undergoing peripheral         revascularization procedures of the lower extremities;         prevention of cardiovascular events in patients with nonvalvular         atrial fibrillation scheduled for cardioversion; reducing the         risk of death, myocardial infarction, or stroke in participants         with heart failure and coronary artery disease following an         episode of decompensated heart failure; preventing major         cardiovascular events in coronary or peripheral artery disease;         reducing the risk of cardiovascular death, myocardial         infarction, or stroke in patients with recent acute coronary         syndrome; prevention of the composite of stroke or systemic         embolism in patients with rheumatic valvular heart disease         (RVHD) with atrial fibrillation or flutter who are unsuitable         for vitamin K antagonist therapy, or in patients with RVHD         without AF or Flutter with at least one of the following: Left         atrial enlargement ≥5.5 cm, Left atrial spontaneous echo         contrast, left atrial thrombus, frequent ectopic atrial activity         (>1000/24 hours) on Holter ECG; prevention of restenosis after         infrainguinal percutaneous transluminal angioplasty for critical         limb ischemia; and decreasing the risk of cardiovascular         disease, myocardial infarction, revascularization, ischemic         stroke, and systemic embolism, essential hypertension,         hypertension, pulmonary hypertension, recurrent and paroxysmal         supraventricular tachycardia, supraventricular tachycardia,         atrial tachycardia, junctional tachycardia, cerebral vasospasm,         hypertrophic cardiomyopathy, chronic stable angina pectoris,         unstable angina pectoris, Prinzmetal variant angina, ventricular         rate control in atrial fibrillation/flutter, cluster headache,         migraine, myocardial infarction in patients with preserved left         ventricular function, management of manic manifestations of         bipolar disorder, Raynaud's disease, coronary artery disease,         subarachnoid hemorrhage, Dravet Syndrome, beta cell survival         therapy in Type I diabetes, vestibular migraine, chronic         subjective dizziness, erectile dysfunction, keloid recurrence,         refractory epilepsy, refractory meningioma, chronic heart         failure secondary to non-ischemic cardiomyopathy, relapsed or         refractory Hodgkin lymphoma, Marfan Syndrome,         treatment-resistant mania, kidney disease in diabetic patients,         Metabolic Syndrome, and hypoglycemia following gastric bypass.

212. The method of embodiment 211, wherein the patient who is concomitantly administered rivaroxaban and verapamil is not renally impaired.

213. The method of embodiment 211, wherein the patient who is concomitantly administered rivaroxaban and verapamil is mildly renally impaired.

214. The method of embodiment 211, wherein the patient who is concomitantly administered rivaroxaban and verapamil is moderately renally impaired.

215. The method of embodiment 211, wherein the patient who is concomitantly administered rivaroxaban and verapamil is severely renally impaired.

216. The method of embodiment 211, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 80 mL/min.

217. The method of embodiment 211, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of at least about 90 mL/min.

218. The method of embodiment 211, wherein said patient has a CL_(Cr) of about 50-79 mL/min.

219. The method of embodiment 211, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 60-89 mL/min.

220. The method of embodiment 211, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-49 mL/min.

221. The method of embodiment 211, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 30-59 mL/min.

222. The method of embodiment 211, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 30 mL/min.

223. The method of embodiment 211, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of about 15-29 mL/min.

224. The method of embodiment 211, wherein the patient who is concomitantly administered rivaroxaban and verapamil has a CL_(Cr) of less than about 15 mL/min.

225. The method of embodiment 211, wherein the dose of rivaroxaban is 0% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

226. The method of embodiment 211, wherein the dose of rivaroxaban is at least about 5% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

227. The method of embodiment 211, wherein the dose of rivaroxaban is a percentage of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil, wherein the percentage is selected less than: about 99.5%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, or about 5% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

228. The method of embodiment 211, wherein the dose of rivaroxaban is a percentage of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil, wherein the percentage is at least about: 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

229. The method of embodiment 211, wherein the dose of rivaroxaban recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg, and the dose administered in (b) is no more than: about 19.9 mg, about 19 mg, about 18 mg, about 17.5 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12.5 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2.5 mg, about 2 mg, or about 1 mg.

230. The method of embodiment 211, wherein the dose of rivaroxaban recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg, and the dose administered in (b) is at least: about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 17.5 mg, about 18 mg, or about 19 mg.

231. The method of embodiment 211, wherein said condition treated with the Factor Xa inhibitor is reducing the risk of stroke and systemic embolism in patients with non valvular atrial fibrillation.

232. The method of embodiment 211, wherein said condition treated with the Factor Xa inhibitor is deep vein thrombosis (DVT).

233. The method of embodiment 211, wherein said condition treated with the Factor Xa inhibitor is pulmonary embolism (PE).

234. The method of embodiment 211, wherein said condition treated with the Factor Xa inhibitor is reducing the risk of DVT.

235. The method of embodiment 211, wherein said condition treated with the Factor Xa inhibitor is the prophylaxis of DVT which leads to PE in patients undergoing knee or hip replacement therapy.

236. A method of treating a condition with a Factor Xa inhibitor, comprising:

-   -   (a) optionally administering about 100 to about 480 mg verapamil         daily to the patient; and     -   (b) administering a dose of rivaroxaban to the patient which         provides an AUC which is at or below a target AUC for a         statistical measure of the population to which the patient         belongs;     -   wherein:         -   said condition treated with a Factor Xa inhibitor is any             condition disclosed herein or is a condition selected from             the group consisting of reducing the risk of stroke and             systemic embolism in patients with non valvular atrial             fibrillation, treating deep vein thrombosis (DVT), treating             pulmonary embolism (PE), reducing the risk of DVT, and             reducing the risk of PE, the prophylaxis of DVT which leads             to PE in patients undergoing knee or hip replacement             therapy, and said condition for which a calcium channel             blocker is indicated is the management of essential             hypertension;         -   said target AUC is selected from about 3792, about 3404, or             about 2448 μg·hr/L;         -   said statistical measure of the patient population to which             the patient belongs is the maximum, mean of top 3, upper             boundary of the 90% confidence interval, median, arithmetic             mean, geometric mean, lower boundary of the 90% confidence             interval, or minimum; and         -   the patient populations are patients with normal renal             function concomitantly administered verapamil, patients with             mild renal impairment not concomitantly administered             verapamil, patients with mild renal impairment concomitantly             administered verapamil, patients with moderate renal             impairment not concomitantly administered verapamil,             patients with moderate renal impairment concomitantly             administered verapamil, patients with severe renal             impairment not concomitantly administered verapamil, or             patients with severe renal impairment concomitantly             administered verapamil.

237. A method of treating a condition with a Factor Xa inhibitor and a calcium channel blocker, comprising:

-   -   (a) optionally administering about 100 to about 480 mg verapamil         daily to the patient; and     -   (b) administering a dose of rivaroxaban to the patient which         provides a C_(max) which is at or below a target C_(max) for a         statistical measure of the population to which the patient         belongs;     -   wherein:         -   said condition treated with a Factor Xa inhibitor is any             condition disclosed herein or is a condition selected from             the group consisting of reducing the risk of stroke and             systemic embolism in patients with non valvular atrial             fibrillation, treating deep vein thrombosis (DVT), treating             pulmonary embolism (PE), reducing the risk of DVT, and             reducing the risk of PE, the prophylaxis of DVT which leads             to PE in patients undergoing knee or hip replacement             therapy, and said condition for which a calcium channel             blocker is indicated is the management of essential             hypertension;         -   said target C_(max) is selected from about 317, about 275,             or about 268 ng/mL;         -   said statistical measure of the patient population to which             the patient belongs is the maximum, mean of top 3, upper             boundary of the 90% confidence interval, median, arithmetic             mean, geometric mean, lower boundary of the 90% confidence             interval, or minimum; and         -   the patient populations are patients with normal renal             function concomitantly administered verapamil, patients with             mild renal impairment not concomitantly administered             verapamil, patients with mild renal impairment concomitantly             administered verapamil, patients with moderate renal             impairment not concomitantly administered verapamil,             patients with moderate renal impairment concomitantly             administered verapamil, patients with severe renal             impairment not concomitantly administered verapamil, or             patients with severe renal impairment concomitantly             administered verapamil.

238. A method of treating a condition with a Factor Xa inhibitor and a calcium channel blocker, comprising:

-   -   (a) optionally administering about 100 to about 480 mg verapamil         daily to the patient; and     -   (b) administering a dose of rivaroxaban to the patient, which         after administering said dose of rivaroxaban provides a risk of         major bleeding which is at or below a target risk of major         bleeding for a statistical measure of the population to which         the patient belongs;     -   wherein:         -   said condition treated with the Factor Xa inhibitor is any             condition disclosed herein or is a condition selected from             the group consisting of reducing the risk of stroke and             systemic embolism in patients with non valvular atrial             fibrillation, treating deep vein thrombosis (DVT), treating             pulmonary embolism (PE), reducing the risk of DVT, and             reducing the risk of PE, the prophylaxis of DVT which leads             to PE in patients undergoing knee or hip replacement             therapy, and said condition for which a calcium channel             blocker is indicated is the management of essential             hypertension;         -   said target risk of major bleeding is selected from about             2.8%, about 4.5%, or above about 12%;         -   said statistical measure of the patient population to which             the patient belongs is the maximum, mean of top 3, upper             boundary of the 90% confidence interval, median, arithmetic             mean, geometric mean, lower boundary of the 90% confidence             interval, or minimum; and         -   the patient populations are patients with normal renal             function concomitantly administered verapamil, patients with             mild renal impairment not concomitantly administered             verapamil, patients with mild renal impairment concomitantly             administered verapamil, patients with moderate renal             impairment not concomitantly administered verapamil,             patients with moderate renal impairment concomitantly             administered verapamil, patients with severe renal             impairment not concomitantly administered verapamil, or             patients with severe renal impairment concomitantly             administered verapamil.

239. A method of treating a condition with a Factor Xa inhibitor and a calcium channel blocker, comprising:

-   -   (a) optionally administering about 100 to about 480 mg verapamil         daily to the patient; and     -   (b) administering a dose of rivaroxaban to the patient, which         after administering said dose of rivaroxaban provides a         prothrombin time which is at or below a target prothrombin time         for a statistical measure of the population to which the patient         belongs;     -   wherein:         -   said condition treated with the Factor Xa inhibitor is any             condition disclosed herein or is a condition selected from             the group consisting of reducing the risk of stroke and             systemic embolism in patients with non valvular atrial             fibrillation, treating deep vein thrombosis (DVT), treating             pulmonary embolism (PE), reducing the risk of DVT, and             reducing the risk of PE, the prophylaxis of DVT which leads             to PE in patients undergoing knee or hip replacement             therapy, and said condition for which a calcium channel             blocker is indicated is the management of essential             hypertension;         -   said prothrombin time ranges from about 20 to about 30             seconds;         -   said statistical measure of the patient population to which             the patient belongs is the maximum, mean of top 3, upper             boundary of the 90% confidence interval, median, arithmetic             mean, geometric mean, lower boundary of the 90% confidence             interval, or minimum; and         -   the patient populations are patients with normal renal             function concomitantly administered verapamil, patients with             mild renal impairment not concomitantly administered             verapamil, patients with mild renal impairment concomitantly             administered verapamil, patients with moderate renal             impairment not concomitantly administered verapamil,             patients with moderate renal impairment concomitantly             administered verapamil, patients with severe renal             impairment not concomitantly administered verapamil, or             patients with severe renal impairment concomitantly             administered verapamil.

240. The method of embodiments 236-239, wherein verapamil is replaced with another calcium channel blocker.

241. A method of treating a condition with a Factor Xa inhibitor and a calcium channel blocker, comprising:

-   -   (a) administering rivaroxaban;     -   (b) administering verapamil;     -   (c) reducing the dose of rivaroxaban;     -   wherein after reducing the reducing the dose of rivaroxaban, the         patient exhibits one or more of the following:         -   a steady state rivaroxaban AUC of no more than about 3792             μg·hr/L;         -   a steady state C_(max) of no more than about 317 ng/mL;         -   a risk of major bleeding of no more than about 4.5%;         -   a prothrombin time of 20-30 seconds.

242. The method of embodiment 241, wherein the reduced dose of rivaroxaban is less than the dose of rivaroxaban recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

243. The method of embodiment 242, wherein the reduced dose of rivaroxaban is about 0-99.5% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

244. The method of embodiment 242, wherein the reduced dose of rivaroxaban is 0-19.9 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

245. The method of embodiment 242, wherein the reduced dose of rivaroxaban is 0-14.9 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 15 mg.

246. A method of treating a condition with a Factor Xa inhibitor and a calcium channel blocker, comprising:

-   -   (a) administering verapamil;     -   (b) administering rivaroxaban;     -   (c) reducing the dose of rivaroxaban;     -   wherein after reducing the reducing the dose of rivaroxaban, the         patient exhibits one or more of the following:         -   a steady state rivaroxaban AUC of no more than about 3792             μg·hr/L;         -   a steady state C_(max) of no more than about 317 ng/mL;         -   a risk of major bleeding of no more than about 4.5%;         -   a prothrombin time of 20-30 seconds.

247. A method treating a condition with a Factor Xa inhibitor comprising identifying one or more of the following in a patient concomitantly treated with rivaroxaban and verapamil:

-   -   a steady state rivaroxaban AUC of greater than about 3792         μg·hr/L;     -   a steady state C_(max) of greater than about 317 ng/mL;     -   a risk of major bleeding of greater than about 4.5%;     -   a prothrombin time of more than about 30 seconds; and     -   communicating to the patient that rivaroxaban and verapamil         should not be concomitantly administered.

248. The method of embodiment 247, wherein the dose of rivaroxaban administered to the patient is less than the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

249. The method of embodiment 247, wherein the dose of rivaroxaban administered to the patient is about 0-99.5% of the dose recommended for an otherwise identical (or the same) patient who is not concomitantly administered verapamil.

250. The method of embodiment 247, wherein the dose of rivaroxaban administered to the patient is 0-19.9 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 20 mg.

251. The method of embodiment 247, wherein the dose of rivaroxaban administered to the patient is 0-14.9 mg, and the dose of rivaroxaban recommended for the otherwise identical (or the same) patient who is not concomitantly administered verapamil is 15 mg.

252. The method of embodiment 247, wherein after said communication, verapamil or rivaroxaban administration is stopped.

253. A method of informing a patient concomitantly treated with rivaroxaban and verapamil that the level of rivaroxaban currently administered should be reduced, comprising determining one or more of the following in the patient:

-   -   a steady state rivaroxaban AUC of greater than about 3792         μg·hr/L;     -   a steady state C_(max) of greater than about 317 ng/mL;     -   a risk of major bleeding of greater than about 4.5%;     -   a prothrombin time of more than about 30 seconds; and     -   then communicating to the patient that the dose of rivaroxaban         should be reduced.

254. The method of embodiment 253, wherein after said communication, the dose of rivaroxaban is reduced.

255. The method of embodiment 254, wherein after reducing the dose of rivaroxaban, the patient exhibits one or more of the following:

-   -   a steady state rivaroxaban AUC of no more than about 3792         μg·hr/L;     -   a steady state C_(max) of no more than about 317 ng/mL;     -   a risk of major bleeding of no more than about 4.5%; or     -   a prothrombin time of 20-30 seconds.

256. A method of treating a patient in need of treatment with a Factor Xa inhibitor and a calcium channel blocker, comprising:

-   -   (a) administering about 100 to about 480 mg verapamil daily to         the patient; and     -   (b) administering a dose of rivaroxaban to the patient which is         less than the dose that would be recommended for that patient if         the patient was not concomitantly administered verapamil;     -   wherein after administering the rivaroxaban, the patient         exhibits one or more of the following:         -   a steady state rivaroxaban AUC of no more than about 3792             μg·hr/L;         -   a steady state C_(max) of no more than about 317 ng/mL;         -   a risk of major bleeding of no more than about 4.5%; or         -   a prothrombin time of 20-30 seconds.

257. The method of claim 256, wherein the patient is administered a daily verapamil dose of 120, 240, 360, or 480 mg verapamil.

258. The method of claim 256, wherein the patient is not renally impaired.

259. The method of claim 256, wherein the patient is mildly to severely renally impaired.

260. The method of claim 259, wherein the patient is mildly renally impaired.

261. The method of claim 259, wherein the patient is moderately renally impaired.

262. The method of claim 259, wherein the patient is severely renally impaired.

263. The method of claim 256, wherein the patient has a CL_(Cr) of less than or equal to about 89 mL/min.

264. The method of claim 256, wherein the patient is has a CL_(Cr) of less than or equal to about 79 mL/min.

265. The method of claim 256, wherein the patient is has a CL_(Cr) of 60-89 mL/min.

266. The method of claim 256, wherein the patient is has a CL_(Cr) of 30-59 mL/min.

267. The method of claim 256, wherein the patient is has a CL_(Cr) of 15-29 mL/min.

268. The method of claim 256, wherein the dose of rivaroxaban administered in step (b) ranges from about 16% to about 99.5% of the dose recommended for an otherwise identical patient who is not concomitantly administered verapamil.

269. The method of claim 256, wherein the dose of rivaroxaban recommended for an otherwise identical patient who is not concomitantly administered verapamil is 20 mg, and

-   -   the dose of rivaroxaban administered in step (b) ranges from         about 1 mg to about 19.9 mg.

270. The method of claim 269, wherein the dose of rivaroxaban administered in step (b) is selected from the group consisting of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, and about 17.5 mg.

271. The method of claim 256, wherein the dose of rivaroxaban recommended for an otherwise identical patient who is not concomitantly administered verapamil is 15 mg, and the dose of rivaroxaban administered in step (b) ranges from about 1 mg to about 14.9 mg.

272. The method of claim 271, wherein the dose of rivaroxaban administered in step (b) is selected from the group consisting of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, and about 12.5 mg.

273. The method of claim 256, wherein after administering the rivaroxaban, the patient exhibits two or more of the following:

-   -   a steady state rivaroxaban AUC of no more than about 3792         μg·hr/L;     -   a steady state C_(max) of no more than about 317 ng/mL;     -   a risk of major bleeding of no more than about 4.5%; or     -   a prothrombin time of 20-30 seconds.

274. The method of claim 256, wherein after administering the rivaroxaban, the patient exhibits three or more of the following:

-   -   a steady state rivaroxaban AUC of no more than about 3792         μg·hr/L;     -   a steady state C_(max) of no more than about 317 ng/mL;     -   a risk of major bleeding of no more than about 4.5%; or     -   a prothrombin time of 20-30 seconds.

275. The method of claim 256, wherein after administering the rivaroxaban, the patient exhibits the following:

-   -   a steady state rivaroxaban AUC of no more than about 3792         μg*hr/L;     -   a steady state C_(max) of no more than about 317 ng/mL;     -   a risk of major bleeding of no more than about 4.5%; and     -   a prothrombin time of 20-30 seconds.

276. The method of claim 256, wherein the condition is selected from the group consisting of:

-   -   reducing the risk of stroke and systemic embolism in patients         with non valvular atrial fibrillation,     -   treating deep vein thrombosis (DVT),     -   treating pulmonary embolism (PE),     -   reducing the risk of DVT, and reducing the risk of PE,     -   the prophylaxis of DVT which leads to PE in patients undergoing         knee or hip replacement therapy, and     -   the management of essential hypertension.

277. A method of treating a patient in need of treatment with a Factor Xa inhibitor, comprising:

-   -   administering a dose of rivaroxaban to the patient;     -   wherein the patient is mildly renally impaired, and after         administering the rivaroxaban, the patient exhibits one or more         of the following:         -   a steady state rivaroxaban AUC of no more than about 3792             μg·hr/L;         -   a steady state C_(max) of no more than about 317 ng/mL;         -   a risk of major bleeding of no more than about 4.5%;         -   a prothrombin time of 20-30 seconds.

278. The method of claim 277, wherein the dose of rivaroxaban is less than the recommended dose of rivaroxaban.

279. The method of claim 277, wherein the dose of rivaroxaban ranges from about 16% to about 99.5% of the recommended dose or rivaroxaban.

280. The method of claim 277, wherein the dose of rivaroxaban administered ranges from about 1 mg to about 19.9 mg.

281. The method of claim 280, wherein the dose of rivaroxaban administered is selected from the group consisting of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, and about 17.5 mg.

282. The method of claim 277, wherein the condition is selected from the group consisting of:

-   -   reducing the risk of stroke and systemic embolism in patients         with non valvular atrial fibrillation,     -   treating deep vein thrombosis (DVT),     -   treating pulmonary embolism (PE),     -   reducing the risk of DVT, and reducing the risk of PE,     -   the prophylaxis of DVT which leads to PE in patients undergoing         knee or hip replacement therapy, and     -   the management of essential hypertension.

EXAMPLES Example 1—Oral Verapamil and Rivaroxaban Drug-Drug Interaction

A volunteer patient trial using both healthy and mildly renally impaired subjects is conducted in order to assess the pharmacokinetic and pharmacodynamic consequences of rivaroxaban and verapamil concomitant administration. This initial study is a non-randomized, open label controlled study of the rivaroxaban-verapamil drug-drug interaction.

During the initial portion of the study, patients are administered a single 20 mg dose of rivaroxaban with their breakfast without co-administration of verapamil. These patients are subjected to various one-time and longitudinal pharmacokinetic (PK) and pharmacodynamic (PD) analyses. Patient plasma levels of rivaroxaban are tracked for at least 72 hours after receiving a rivaroxaban dose. C_(max) and AUC values for each dose are calculated. Patients also undergo a general physical exam to determine overall health and well-being.

Additional pharmacodynamic metrics are also gathered for each patient, including, but not limited to: prothrombin time (using the STA® Neoplastin® method) and Factor Xa activity. Protocols for each of these analyses have been described in (Nielsen et al 2015. Renal Function and non-vitamin K oral anticoagulants in comparison with warfarin on safety and efficacy outcomes in atrial fibrillation patients: a systemic review and meta-regression analysis. Clin Res Cardiol May 104(5): 418-429).

During the second portion of the study, patients are administered a verapamil dose of 180 mg on Day 8, 240 mg on Day 9, and 360 mg on Days 10-15 to achieve steady state plasma concentrations of verapamil. On Day 15, patients will receive 360 mg verapamil together with the 20 mg rivaroxaban doses described for the initial portion of the study. All the pharmacokinetic and pharmacodynamics analyses are repeated on patients receiving this treatment.

PK and PD results for the rivaroxaban single treatment and rivaroxaban-verapamil concomitant treatment are compared to determine the safety profile of the resulting rivaroxaban doses.

The results show that concomitant administration of verapamil with rivaroxaban produces higher rivaroxaban plasma concentrations, prolonged PT, and increased Factor Xa inhibition.

Example 2—Pharmacokinetics and Plasma Rivaroxaban Concentrations in Subjects with Mild Renal Impairment and Normal Renal Function

To estimate the effect of steady-state verapamil on the pharmacokinetics, pharmacodynamics, and safety of rivaroxaban, a study was conducted on subjects with either mild renal impairment or normal renal function. Subjects with either mild renal impairment or with normal renal function were enrolled. Subjects received a single 20 mg dose of rivaroxaban (“Period I”) on the first day of the study, and after a washout period, a single 20 mg dose of rivaroxaban and a 360 mg dose of verapamil at steady state (“Period III”).

Renal function of the subjects was determined by measuring creatinine clearance (CLCr) rates. Subjects who had CLCr≥90 ml/min were categorized as having normal renal function whereas subjects who had CLCr 50-79 ml/min were categorized as mild renal impaired. Blood samples were collected and processed according to the standard protocols. Plasma rivaroxaban concentrations were measured on Day 1 of the study at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours, Day 2 at 24 and 36 hours, Day 3 at 48 hours, and Day 4 at 72 hours and are shown in Tables 1A-8 below.

TABLE 1A Plasma Rivaroxaban Concentration-Time Data and Summary Statistics for Treatment Period I Separated by Renal Function Group (PK Analysis Set) Group 1: Mild Renal Impairment, (N = 14) Time Point Day 1, Day 1, Day 1, Day 1, Day 1, Day 1, Day 1, Subject 0 hr 0.5 hr 1 hr 2 hr 3 hr 4 hr 6 hr 1101 0 83.8 151 251 241 218 114 1102 0 207 278 207 197 204 161 1103 0 170 187 185 196 181 126 1104 0 235 218 184 199 182 119 1106 0 24.0 153 232 238 172 172 1108 0 174 168 170 297 344 274 1110 0 201 306 248 206 219 157 1111 0 245 247 211 268 247 164 1114 0 215 308 232 184 192 103 1115 0 170 133 187 215 190 133 1116 0 130 132 120 97.9 90.6 55.7 1118 0 326 448 333 315 316 128 2101 0 208 217 208 176 165 114 2104 0 23.4 25.7 40.6 55.8 79.6 232 n 14 14 14 14 14 14 14 n < LLOQ 14 0 0 0 0 0 0 CV % NC 48.8 48.3 33.4 33.6 35.7 37.3 AM 0 172 212 201 206 200 147 SD 0 84.0 102 66.9 69.2 71.5 54.6 Median 0 188 202 208 202 191 130 Minimum 0 23.4 25.7 40.6 55.8 79.6 55.7 Maximum 0 326 448 333 315 344 274 Lower limit of quantitation (LLOQ) = 5 (μg/L). N: Number of subjects, n: Number of non-missing observations, hr: Hour, BLQ: Below the limit of quantitation, AM: Arithmetic mean, SD: Standard deviation. BLQ values are treated as zero. NC = Not calculated Values expressed in μg/L CV % = (SD/Mean) × 100, where SD and mean are standard deviation and arithmetic mean of untransformed data. Summary statistics for Day 1, 0 hr are based on greater than 30% imputed values. n < LLOQ = Number of BLQs imputed as zero.

TABLE 1B Plasma Rivaroxaban Concentration-Time Data and Summary Statistics for Treatment Period I Separated by Renal Function Group (PK Analysis Set) Group 1: Mild Renal Impairment, (N = 14) Time Point Day 1, Day 1, Day 2, Day 2, Day 3, Day 4, Subject 8 hr 12 hr 24 hr 36 hr 48 hr 72 hr 1101 76.8 52.9 36.5 14.9 8.49 0 1102 131 84.9 53.7 10.0 9.67 0 1103 124 61.5 52.9 8.92 0 0 1104 89.5 38.8 41.9 10.8 6.49 0 1106 157 92.7 19.9 12.1 6.13 0 1108 221 132 50.3 17.9 11.4 0 1110 143 89.1 52.5 21.7 17.0 0 1111 125 72.7 38.6 18.5 15.5 0 1114 66.4 66.8 39.1 14.8 6.71 0 1115 122 103 33.9 11.2 0 0 1116 47.6 29.4 10.1 0 0 0 1118 102 49.9 42.2 21.5 21.4 12.2 2101 90.2 51.9 21.1 7.44 7.10 0 2104 223 97.7 18.0 0 0 0 n 14 14 14 14 14 14 n < LLOQ 0 0 0 2 4 13 CV % 42.2 38.7 39.1 56.1 86.2 374 AM 123 73.1 36.5 12.1 7.85 0.871 SD 51.8 28.3 14.3 6.80 6.77 3.26 Median 123 69.8 38.8 11.6 6.90 0 Minimum 47.6 29.4 10.1 0 0 0 Maximum 223 132 53.7 21.7 21.4 12.2 Lower limit of quantitation (LLOQ) = 5 (μg/L). N: Number of subjects, n: Number of non-missing observations, hr: Hour, BLQ: Below the limit of quantitation, AM: Arithmetic mean, SD: Standard deviation. BLQ values are treated as zero. Values expressed in μg/L CV % = (SD/Mean) × 100, where SD and mean are standard deviation and arithmetic mean of untransformed data. Summary statistics for Day 4, 72 hr are based on greater than 30% imputed values. n < LLOQ = Number of BLQs imputed as zero.

TABLE 2A Plasma Rivaroxaban Concentration-Time Data and Summary Statistics for Treatment Period I Separated by Renal Function Group Excluding Outlier Sample (PK Analysis Set) Group 2: Normal Renal Function, (N = 13) Time Point Day 1, Day 1, Day 1, Day 1, Day 1, Day 1, Day 1, Subject 0 hr 0.5 hr 1 hr 2 hr 3 hr 4 hr 6 hr 01105 0 107 160 187 290 336 230 01107 0 194 252 229 242 297 172 01109 0 117 249 204 307 276 162 01112 0 71.8 175 195 183 169 119 01113 0 169 178 163 183 148 91.9 01117 0 429 297 195 164 155 116 01119 0 197 175 208 263 352 180 01120 0 60.3 214 196 211 187 131 01121 0 218 195 151 133 115 67.5 02102 0 67.1 142 212 202 171 142 02103 0 129 214 201 230 183 133 02105 0 43.4 104 188 245 292 256 02106 0 26.2 80.5 141 215 266 218 n 13 13 13 13 13 13 13 n < LLOQ 13 0 0 0 0 0 0 CV % NC 75.9 32.0 13.1 22.4 34.8 35.5 AM 0 141 187 190 221 227 155 SD 0 107 59.9 24.8 49.5 78.8 55.1 Median 0 117 178 195 215 187 142 Minimum 0 26.2 80.5 141 133 115 67.5 Maximum 0 429 297 229 307 352 256 Lower limit of quantitation (LLOQ) = 5 (μg/L). N: Number of subjects, n: Number of non-missing observations, hr: Hour, BLQ: Below the limit of quantitation, AM: Arithmetic mean, SD: Standard deviation. % CVb = 100 * SQRT [ex[(S{circumflex over ( )}2) − 1]], where S is the standard deviation of the data on a log scale. BLQ values are treated as zero. NC = Not calculated Values expressed in μg/L Summary statistics for Day 1, 0 hr are based on greater than 30% imputed values. n < LLOQ = Number of BLQs imputed as zero.

TABLE 2B Plasma Rivaroxaban Concentration-Time Data and Summary Statistics for Treatment Period I Separated by Renal Function Group Excluding Outlier Sample (PK Analysis Set) Group 2: Normal Renal Function, (N = 13) Time Point Day 1, Day 1, Day 2, Day 2, Day 3, Day 4, Subject 8 hr 12 hr 24 hr 36 hr 48 hr 72 hr 01105 202 94.7 27.1 9.61 0 0 01107 114 72.3 25.1 5.30 0 0 01109 138 110 23.8 0 0 0 01112 88.9 53.9 20.0 6.02 0 0 01113 71.5 26.5 21.3 7.48 0 0 01117 104 47.3 32.0 20.6 14.3 0 01119 138 77.3 24.3 7.19 93.1† 0 01120 114 50.7 17.3 5.98 0 0 01121 52.7 38.0 19.4 9.86 7.00 0 02102 109 66.6 22.6 5.26 0 0 02103 134 42.6 16.6 8.97 5.53 0 02105 183 91.9 25.2 8.16 5.53 0 02106 150 86.9 35.4 12.4 8.51 0 n 13 13 13 13 12 13 n < LLOQ 0 0 0 1 7 13 CV % 33.7 38.2 22.7 58.0 139 NC AM 123 66.1 23.9 8.22 3.41 0 SD 41.4 25.3 5.42 4.76 4.75 0 Median 114 66.6 23.8 7.48 0 0 Minimum 52.7 26.5 16.6 0 0 0 Maximum 202 110 35.4 20.6 14.3 0 Lower limit of quantitation (LLOQ) = 5 (μg/L). N: Number of subjects, n: Number of non-missing observations, hr: Hour, BLQ: Below the limit of quantitation, AM: Arithmetic mean, SD: Standard deviation. % CVb = 100 * SQRT [ex[(S{circumflex over ( )}2) − 1]], where S is the standard deviation of the data on a log scale. BLQ values are treated as zero. NS = No sample; NC = Not calculated Values expressed in μg/L †Outlier sample excluded from summary statitics Summary statistics for Day 3, 48 hr, Day 4, 72 hr are based on greater than 30% imputed values. n < LLOQ = Number of BLQs imputed as zero.

TABLE 3A Plasma Rivaroxaban Concentration-Time Data and Summary Statistics for Treatment Period III Separated by Renal Function Group (PK Analysis Set) Group 1: Mild Renal Impairment, (N = 11) Time Point Day 1, Day 1, Day 1, Day 1, Day 1, Day 1, Day 1, Subject 0 hr 0.5 hr 1 hr 2 hr 3 hr 4 hr 6 hr 1101 0 154 211 196 238 247 154 1103 0 203 293 300 285 257 188 1104 0 278 260 268 276 214 164 1106 0 10.2 42.6 109 213 280 233 1108 0 158 192 263 303 303 269 1111 0 242 272 278 280 327 285 1114 0 249 218 279 250 226 170 1116 0 185 192 191 203 242 124 1118 0 349 387 429 429 458 209 2101 0 202 190 149 134 160 99.7 2104 0 136 113 132 117 126 135 n 11 11 11 11 11 11 11 n < LLOQ 11 0 0 0 0 0 0 CV % NC 44.4 42.2 39.1 34.3 34.1 32.1 AM 0 197 216 236 248 258 185 SD 0 87.5 91.0 92.1 85.1 88.1 59.2 Median 0 202 211 263 250 247 170 Minimum 0 10.2 42.6 109 117 126 99.7 Maximum 0 349 387 429 429 458 285 Lower limit of quantitation (LLOQ) = 5 (μg/L). N: Number of subjects, n: Number of non-missing observations, hr: Hour, BLQ: Below the limit of quantitation, AM: Arithmetic mean, SD: Standard deviation. BLQ values are treated as zero. NC = Not calculated Values expressed in μg/L CV % = (SD/Mean) × 100, where SD and mean are standard deviation and arithmetic mean of untransformed data. Summary statistics for Day 1, 0 hr are based on greater than 30% imputed values. n < LLOQ = Number of BLQs imputed as zero.

TABLE 3B Plasma Rivaroxaban Concentration-Time Data and Summary Statistics for Treatment Period III Separated by Renal Function Group (PK Analysis Set) Group 1: Mild Renal Impairment, (N = 11) Time Point Day 1, Day 1, Day 2, Day 2, Day 3, Day 4, Subject 8 hr 12 hr 24 hr 36 hr 48 hr 72 hr 1101 125 77.7 36.0 11.1 8.48 0 1103 148 96.0 61.9 20.2 11.1 0 1104 194 88.6 45.5 25.0 12.9 8.27 1106 251 145 34.8 21.6 8.48 0 1108 222 154 78.5 33.0 27.4 10.6 1111 268 159 76.8 29.1 23.0 9.37 1114 126 55.4 27.6 14.2 17.0 8.69 1116 106 67.7 30.0 13.9 8.27 0 1118 179 134 68.5 34.9 31.2 13.1 2101 78.5 75.8 62.2 31.1 14.7 0 2104 118 95.0 46.6 27.0 19.1 7.48 n 11 11 11 11 11 11 n < LLOQ 0 0 0 0 0 5 CV % 37.8 35.4 36.2 34.5 47.9 99.6 AM 165 104 51.7 23.7 16.5 5.23 SD 62.3 37.0 18.7 8.19 7.91 5.21 Median 148 95.0 46.6 25.0 14.7 7.48 Minimum 78.5 55.4 27.6 11.1 8.27 0 Maximum 268 159 78.5 34.9 31.2 13.1 Lower limit of quantitation (LLOQ) = 5 (μg/L). N: Number of subjects, n: Number of non-missing observations, hr: Hour, BLQ: Below the limit of quantitation, AM: Arithmetic mean, SD: Standard deviation. BLQ values are treated as zero. Values expressed in μg/L CV % = (SD/Mean) × 100, where SD and mean are standard deviation and arithmetic mean of untransformed data. Summary statistics for Day 4, 72 hr are based on greater than 30% imputed values. n < LLOQ = Number of BLQs imputed as zero.

TABLE 4A Plasma Rivaroxaban Concentration-Time Data and Summary Statistics for Treatment Period III Separated by Renal Function Group (PK Analysis Set) Group 2: Normal Renal Function, (N = 10) Time Point Day Day Day Day Day Day Day 1, 1, 1, 1, 1, 1, 1, Subject 0 hr 0.5 hr 1 hr 2 hr 3 hr 4 hr 6 hr 1105 0 179 185 208 267 383 268 1107 0 179 159 220 331 296 303 1109 0 198 236 302 264 292 205 1112 0 151 163 160 163 143 116 1119 0 148 206 314 314 348 287 1120 0 131 137 236 260 257 202 1121 0 178 201 208 178 154 103 2102 0 125 141 225 220 224 193 2103 0 214 269 232 225 201 177 2106 0 50.9 122 284 310 394 227 n 10 10 10 10 10 10 10 n < LLOQ 10 0 0 0 0 0 0 CV % NC 29.9 25.7 19.9 22.4 33.2 32.0 AM 0 155 182 239 253 269 208 SD 0 46.4 46.7 47.6 56.8 89.5 66.6 Median 0 164 174 228 262 274 204 Minimum 0 50.9 122 160 163 143 103 Maximum 0 214 269 314 331 394 303 Lower limit of quantitation (LLOQ) = 5 (μg/L). N: Number of subjects, n: Number of non-missing observations, hr: Hour, BLQ: Below the limit of quantitation, AM: Arithmetic mean, SD: Standard deviation. BLQ values are treated as zero. NC = Not calculated Values expressed in μg/L CV % = (SD/Mean) × 100, where SD and mean are standard deviation and arithmetic mean of untransformed data. Summary statistics for Day 1, 0 hr are based on greater than 30% imputed values. n < LLOQ = Number of BLQs imputed as zero.

TABLE 4B Plasma Rivaroxaban Concentration-Time Data and Summary Statistics for Treatment Period III Separated by Renal Function Group (PK Analysis Set) Group 2: Normal Renal Function, (N = 10) Time Point Day Day Day Day Day Day 1, 1, 2, 2, 3, 4, Subject 8 hr 12 hr 24 hr 36 hr 48 hr 72 hr 1105 197 85.9 42.3 13.3 5.04 0 1107 182 121 41.3 11.7 6.36 0 1109 143 110 42.5 17.4 10.8 0 1112 94.9 78.7 50.9 12.3 8.87 0 1119 262 145 27.3 8.79 0 0 1120 119 62.8 27.4 8.99 0 0 1121 73.9 50.8 27.1 14.8 12.2 0 2102 160 102 48.4 19.5 10.7 0 2103 248 98.4 40.6 12.1 6.73 6.42 2106 173 125 60.2 22.8 13.0 9.22 n 10 10 10 10 10 10 n < LLOQ 0 0 0 0 2 8 CV % 36.9 29.7 27.0 31.9 63.3 215 AM 165 98.0 40.8 14.2 7.37 1.56 SD 61.0 29.1 11.0 4.52 4.66 3.36 Median 166 100 41.8 12.8 7.80 0 Minimum 73.9 50.8 27.1 8.79 0 0 Maximum 262 145 60.2 22.8 13.0 9.22 Lower limit of quantitation (LLOQ) = 5 (μg/L). N: Number of subjects, n: Number of non-missing observations, hr: Hour, BLQ: Below the limit of quantitation, AM: Arithmetic mean, SD: Standard deviation. BLQ values are treated as zero. Values expressed in μg/L CV % = (SD/Mean) × 100, where SD and mean are standard deviation and arithmetic mean of untransformed data. Summary statistics for Day 4, 72 hr are based on greater than 30% imputed values. n < LLOQ = Number of BLQs imputed as zero.

Plasma rivaroxaban pharmacokinetic data for both normal renal function groups and mild renal impairment groups who received both rivaroxaban alone (Period I) and rivaroxaban and verapamil (Period III) are presented in the Tables below:

TABLE 5 Plasma Rivaroxaban Noncompartmental Pharmacokinetic Parameters and Summary Statistics for Treatment Period I Separated by Renal Function Group (PK Analysis Set) Group 1: Mild Renal Impairment, (N = 14) C_(max) t_(max) AUC_(0-t) AUC_(0-inf) K_(el) t_(1/2) CL/F CL/F/kg V_(z)/F Subject (ng/mL) (hr) (hr*ng/mL) (hr*ng/mL) (1/hr) (hr) (L/hr) ((L/hr)/kg) (L) 01101 251 2.00 2530 2680 0.0542 12.8 7.45 0.113 138 01102 278 1.00 3240 3370 0.0734 9.44 5.93 0.0803 80.8 01103 196 3.00 2690 2800 0.0825 8.40 7.14 0.114 86.5 01104 235 0.50 2430 2510 0.0752 9.21 7.96 0.156 106 01106 238 3.00 2830 2960 0.0491 14.1 6.76 0.0845 138 01108 344 4.00 4350 4500 0.0778 8.91 4.45 0.0496 57.2 01110 306 1.00 3560 3840 0.0601 11.5 5.20 0.0670 86.5 01111 268 3.00 3250 3600 0.0447 15.5 5.55 0.0841 124 01114 308 1.00 2670 2760 0.0734 9.44 7.24 0.137 98.7 01115 215 3.00 2800 2920 0.0925 7.50 6.84 0.0946 74.0 01116 132 1.00 1070 1170 0.0954 7.26 17.0 0.253 179 01118 448 1.00 3880 4390 0.0240 28.9 4.56 0.0828 190 02101 217 1.00 2200 2290 0.0786 8.82 8.74 NR 111 02104 232 6.00 2290 2400 0.155 4.47 8.32 NR 53.7 n 14 14 14 14 14 14 14 12 14 GM* 252 NC 2720 2880 0.0683 10.2 6.95 0.100 102 CVb % 28.7 NC 28.3 29.1 41.1 52.5 41.9 49.2 38.0 AM 262 NC 2840 3010 0.0740 11.2 7.37 0.110 109 SD 75.2 NC 804 878 0.0304 5.87 3.09 0.0540 41.3 Median 244 1.50 2750 2860 0.0743 9.32 6.99 0.0896 102 Minimum 132 0.50 1070 1170 0.0240 4.47 4.45 0.0496 53.7 Maximum 448 6.00 4350 4500 0.155 28.9 17.0 0.253 190 *Calculated using log transformed data. N: Number of subjects, n: Number of non-missing observations, GM: Geometric mean, AM: Arithmetic mean, SD: Standard deviation, NR = Not reported; NC = Not calculated % CVb = 100 * SQRT [ex[(S{circumflex over ( )}2) − 1]], where S is the standard deviation of the data on a log scale.

TABLE 6 Plasma Rivaroxaban Noncompartmental Pharmacokinetic Parameters and Summary Statistics for Treatment Period I Separated by Renal Function Group Excluding Outlier Sample (PK Analysis Set) Group 2: Normal Renal Function, (N = 13) C_(max) t_(max) AUC_(0-t) AUC_(0-inf) K_(el) t_(1/2) CL/F CL/F/kg V_(z)/F Subject (ng/mL) (hr) (hr*ng/mL) (hr*ng/mL) (1/hr) (hr) (L/hr) ((L/hr)/kg) (L) 01105 336 4.08 3370 3470 0.0955 7.26 5.76 0.0696 60.4 01107 297 4.00 2800 2850 0.110 6.29 7.02 0.0817 63.7 01109 307 3.00 2930 3150 0.108 6.39 6.35 0.0829 58.6 01112 195 2.00 2010 2070 0.0938 7.39 9.64 0.0960 103 01113 183 3.00 1700 1790 0.0839 8.26 11.2 0.197 133 01117 429 0.50 2670 3090 0.0336 20.6 6.46 0.0998 193 01119 352 4.10 3560 4440 0.106 6.56 4.50 0.0579 42.6 01120 214 1.00 2130 2200 0.0891 7.78 9.10 0.107 102 01121 218 0.50 1700 1840 0.0511 13.6 10.9 0.177 213 02102 212 2.00 2260 2310 0.108 6.44 8.68 NR 80.5 02103 230 3.00 2280 2400 0.0458 15.1 8.33 NR 182 02105 292 4.00 3200 3260 0.0939 7.38 6.14 NR 65.4 02106 266 4.00 3040 3150 0.0726 9.55 6.34 NR 87.4 n 13 13 13 13 13 13 13 9 13 GM* 263 NC 2520 2680 0.0793 8.74 7.47 0.0997 94.2 CVb % 26.7 NC 24.0 27.4 30.5 46.3 26.8 44.3 53.0 AM 272 NC 2590 2770 0.0839 9.43 7.72 0.108 106 SD 72.4 NC 621 760 0.0256 4.37 2.07 0.0476 56.4 Median 266 3.00 2670 2850 0.0938 7.39 7.02 0.0960 87.4 Minimum 183 0.50 1700 1790 0.0336 6.29 4.50 0.0579 42.6 Maximum 429 4.10 3560 4440 0.110 20.6 11.2 0.197 213 *Calculated using log transformed data. N: Number of subjects, n: Number of non-missing observations, GM: Geometric mean, AM: Arithmetic mean, SD: Standard deviation, NR = Not reported; NC = Not calculated % CVb = 100 * SQRT [ex[(S{circumflex over ( )}2) − 1]], where S is the standard deviation of the data on a log scale. The Period 1, 48 hr timepoint for subject 01119 was excluded as an outlier from the analysis.

TABLE 7 Plasma Rivaroxaban Noncompartmental Pharmacokinetic Parameters and Summary Statistics for Treatment Period III Separated by Renal Function Group (PK Analysis Set) Group 1: Mild Renal Impairment, (N = 11) C_(max) t_(max) AUC_(0-t) AUC_(0-inf) K_(el) t_(1/2) CL/F CL/F/kg V_(z)/F Subject (ng/mL) (hr) (hr*ng/mL) (hr*ng/mL) (1/hr) (hr) (L/hr) ((L/hr)/kg) (L) 01101 247 4.00 2950 3070 0.0721 9.61 6.51 0.0991 90.3 01103 300 2.00 3920 4090 0.0664 10.4 4.89 0.0781 73.6 01104 278 0.50 3990 4140 0.0542 12.8 4.83 0.0949 89.1 01106 280 4.00 3870 3980 0.0820 8.46 5.03 0.0628 61.3 01108 303 3.00 5630 5840 0.0503 13.8 3.42 0.0382 68.1 01111 327 4.00 5810 6090 0.0323 21.4 3.28 0.0497 102 01114 279 2.00 3230 3530 0.0283 24.5 5.66 0.107 200 01116 242 4.00 2680 2820 0.0590 11.7 7.08 0.105 120 01118 458 4.00 5990 6300 0.0418 16.6 3.17 0.0577 76.0 02101 202 0.50 3010 3260 0.0598 11.6 6.14 NR 103 02104 136 0.50 3280 3480 0.0374 18.5 5.74 NR 154 n 11 11 11 11 11 11 11 9 11 GM* 267 NC 3880 4080 0.0504 13.7 4.90 0.0728 97.1 CVb % 28.9 NC 30.2 29.6 32.0 35.6 26.2 33.6 40.2 AM 277 NC 4030 4240 0.0530 14.5 5.07 0.0770 103 SD 80.1 NC 1220 1260 0.0170 5.16 1.33 0.0259 41.5 Median 279 3.00 3870 3980 0.0542 12.8 5.03 0.0781 90.3 Minimum 136 0.50 2680 2820 0.0283 8.46 3.17 0.0382 61.3 Maximum 458 4.00 5990 6300 0.0820 24.5 7.08 0.107 200 *Calculated using log transformed data. N: Number of subjects, n: Number of non-missing observations, GM: Geometric mean, AM: Arithmetic mean, SD: Standard deviation. NR = Not reported; NC = Not calculated % CVb = 100 * SQRT [ex[(S{circumflex over ( )}2) − 1]], where S is the standard deviation of the data on a log scale.

TABLE 8 Plasma Rivaroxaban Noncompartmental Pharmacokinetic Parameters and Summary Statistics for Treatment Period III Separated by Renal Function Group (PK Analysis Set) Group 2: Normal Renal Function, (N = 10) C_(max) t_(max) AUC_(0-t) AUC_(0-inf) K_(el) t_(1/2) CL/F CL/F/kg V_(z)/F Subject (ng/mL) (hr) (hr*ng/mL) (hr*ng/mL) (1/hr) (hr) (L/hr) ((L/hr)/kg) (L) 01105 383 4.00 3780 3840 0.0884 7.84 5.21 0.0629 58.9 01107 331 3.00 3990 4060 0.0866 8.00 4.92 0.0573 56.9 01109 302 2.00 3770 3930 0.0672 10.3 5.08 0.0664 75.7 01112 163 1.00 2690 2820 0.0656 10.6 7.08 0.0705 108 01119 348 4.00 4260 4330 0.121 5.71 4.61 0.0594 38.0 01120 260 3.00 2690 2800 0.0810 8.55 7.14 0.0839 88.1 01121 208 2.00 2260 2530 0.0456 15.2 7.90 0.128 173 02102 225 2.00 3500 3670 0.0643 10.8 5.46 NR 84.9 02103 269 1.00 3780 3880 0.0614 11.3 5.15 NR 83.9 02106 394 4.00 4620 4800 0.0511 13.6 4.17 NR 81.6 n 10 10 10 10 10 10 10 7 10 GM* 278 NC 3460 3600 0.0705 9.83 5.56 0.0727 78.8 CVb % 26.6 NC 21.4 19.9 30.0 27.6 21.9 33.0 43.2 AM 288 NC 3530 3670 0.0732 10.2 5.67 0.0755 84.9 SD 76.8 NC 755 728 0.0220 2.82 1.24 0.0249 36.7 Median 286 2.50 3780 3860 0.0664 10.4 5.18 0.0664 82.7 Minimum 163 1.00 2260 2530 0.0456 5.71 4.17 0.0573 38.0 Maximum 394 4.00 4620 4800 0.121 15.2 7.90 0.128 173 *Calculated using log transformed data. N: Number of subjects, n: Number of non-missing observations, GM: Geometric mean, AM: Arithmetic mean, SD: Standard deviation. NR = Not reported; NC = Not calculated % CVb = 100 * SQRT [ex[(S{circumflex over ( )}2) − 1]], where S is the standard deviation of the data on a log scale.

Example 3—Plasma Rivaroxaban Concentrations and the Risk of Major Bleeding in Subjects with Mild Renal Impairment

To evaluate the relationship between the plasma levels of rivaroxaban and the risk of major bleeding, the subjects with mild renal insufficiency were given a single 20 mg dose of rivaroxaban on the first day of the study (as described in the study in Example 2). Blood samples were collected and processed according to the standard protocols. Plasma rivaroxaban concentrations were measured on Day 1 and Day 15. As shown in FIGS. 1 and 2, the risk of major bleeding based on PT values, were positively correlated with increased plasma concentrations of rivaroxaban. The results showed a clear linear relationship between the pharmacokinetic and the pharmacodynamics of rivaroxaban in subjects with normal renal function and mild renal insufficiency.

The steady state area under the curve (AUC) of plasma rivaroxaban in subjects with either normal renal function or mild renal impairment under different treatment regimens was also examined. As shown in FIG. 3, the leftmost 6 box plots (study 10842) show the distribution of AUC values for various dosing levels of rivaroxaban (10 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg, respectively) previously measured in clinical trials supporting FDA approval of Xarelto® (rivaroxaban). The next nine box plots (studies 10993, 10999, 12359, 12680, 11273, 10989, and 11938) in the middle represent subjects treated with a single 20 mg dose of rivaroxaban under normal, fasted, or fed condition. All show the geometric mean plus or minus one standard deviation. The last four box plots show the distribution of AUC values measured in the present study, for subjects with normal renal function (designated “N”) and subjects with mild renal impairment (designated “MRI”) who were either treated with a single 20 mg dose of rivaroxaban (“P1”) or a single 20 mg dose of rivaroxaban and 360 mg verapamil (“P3”). These four show the geometric mean and the full minimum and maximum subject value range.

The results in FIG. 3 show that the geometric mean in the subjects with mild renal impairment treated with both rivaroxaban and verapamil in the present study was about one standard deviation higher than the mean AUC levels in subjects with normal renal function treated with a single 80 mg dose of rivaroxaban. The present study shows that subjects with mild renal impairment who took both rivaroxaban and verapamil had mean AUC levels well above the AUC levels observed in subjects with normal renal function treated with a single 20 mg dose of rivaroxaban; that is, such patients coadministered rivaroxaban and verapamil have AUC values substantially higher than values currently considered acceptable by the FDA.

Another representation of these data are shown in FIG. 4. Label “A” represents the upper bound of the 90% confidence interval of the steady state AUC of patients administered 20 mg of rivaroxaban, about 3,792 μg·hr/L. Label “B” is the estimated steady state AUC, about 3,404 μg·hr/L for patients administered a single 10 mg dose of rivaroxaban in combination with a strong CYP3A4/Pgp inhibitor. Label “C” is the upper boundary of the 90% confidence interval of the steady state AUC level in subjects treated with a single 20 mg dose of rivaroxaban after a meal, about 2,448 μg·hr/L. The remaining 4 box plots are reproduced from FIG. 3. FIG. 4 shows that AUC_(inf) values in subjects with mild renal impairment (“MRI”) treated with a single 20 mg dose of rivaroxaban and 360 mg verapamil (P3) are significantly higher than expected from previous studies. For example, the geometric mean of the steady state AUC for such patients was higher than the upper limits of safety identified in the FDA's Clinical Pharmacology review for rivaroxaban, demonstrating that a significant portion of the relevant patient population who have mild renal impairment have AUC values falling outside of the range accepted by the FDA. Further, the present study shows that a significant portion of patients with normal renal function treated with rivaroxaban and verapamil have plasma levels significantly higher than the upper boundary of the 90% confidence interval of the steady state AUC level in subjects from the rivaroxaban approval studies treated with a single 20 mg dose of rivaroxaban (Label “C”), demonstrating a higher bleeding risk than is presently recognized in the art. Additionally, the present study shows that patients with mild renal impairment have plasma levels of rivaroxaban which are significantly higher than the upper boundary of the 90% confidence interval of the steady state AUC level in subjects from the rivaroxaban approval studies treated with a single 20 mg dose of rivaroxaban (Label “C”), demonstrating a higher bleeding risk than is presently recognized in the art.

FIG. 5 shows that the relationship between steady state rivaroxaban AUC and the risk of major bleeding. Group “a” in FIG. 5 represents the average geometric mean of fed subjects across two studies (10989 and 11938) who took a single 20 mg rivaroxaban and had an average of AUC of approximately 2,026 μg·hr/L, which corresponded to about 3% risk of major bleeding. Group “b” in the FIG. 5 represents subjects with mild renal impairment who took a single 20 mg rivaroxaban and 360 mg verapamil and had an estimated of AUC_(inf) of approximately 5,469 g·hr/L, which shows that the mild renal impairment caused higher accumulation of rivaroxaban in the plasma and led to 2.5 times higher the risk of major bleeding compared to the populations in Group “a”. Group “c” represents the average of the three subjects in Group “b” who had the highest AUC_(inf), which was about 8,143 g·hr/L. The risk of major bleeding of the subjects in Group “c” were at least 5 times higher compared to the populations in Group “a” and not even visible on this scale.

Example 4—Mathematical Models for Determining the Redosing Regimens of Rivaroxaban to Reduce the Risk of Major Bleeding in Subjects with Mild Renal Impairment

To reduce the risks of major bleeding for the various populations that are among the high risk groups identified above, Applicants created an exponential mathematical model and a logarithmic mathematical model to calculate the appropriate rivaroxaban redosing regimens for these populations to achieve the AUC and C_(max) that are within the safety recommendations.

The present study has identified various target AUC values representing different potential AUC levels above which there could be a serious risk of bleeding in patients treated with rivaroxaban as described herein. Specifically, referring to FIG. 4, AUC values above about 3,792 μg·hr/L (the upper bound of the 90% confidence interval of the steady state AUC of patients administered 20 mg of rivaroxaban, Label “A”), above about 3,404 μg·hr/L (estimated steady state AUC for patients administered a single 10 mg dose of rivaroxaban in combination with a strong CYP3A4/Pgp inhibitor, Label “B”), or about 2,448 μg·hr/L (the upper boundary of the 90% confidence interval of the steady state AUC level in subjects with normal renal function treated with a single 20 mg dose of rivaroxaban after a meal, Label “C”) are all potential AUC values above which there would be an unacceptable level of bleeding risk.

It is well known that the pharmacokinetics characteristics of drugs vary among individuals. Thus, PK parameters such as AUC_(inf) and C_(max) within a patient population or subgroup are characterized statistically, using parameters such as the maximum and minimum values, mean (arithmetic and geometric), median, average of the highest 3 levels in the patient population, and the 90% confidence interval (having an upper and lower boundary or limit). When assessing risks associated with drug treatments (e.g., bleeding risk associated with rivaroxaban treatment), it may be desirable to ensure that the entire patient population has AUC (or C_(max)) values falling below the level identified as unacceptably risky (e.g., termed the “target” value. In this case, the drug should be dosed such that the maximum AUC or C_(max) value in the population or subgroup falls at or below the target value. In other estimates of risk, the drug should be dosed such that other statistical parameters characterizing the appropriate PK values of the patient population (mean, median, 90% confidence interval boundaries) fall at or below the target value. As shown below in Tables 9-124, the present applicants have calculated, based on various models, the maximum rivaroxaban dose for various patients (e.g., having varying levels of renal impairment and/or concomitant treatment with verapamil) which will provide AUC_(inf) or C_(max) values no higher than the “target” AUC_(inf) or C_(max) value, for the respective statistical parameter characterizing the PK distribution of the patient population. That is, for a particular patient population and target value (AUC or C_(max)), applicants have calculated the maximum rivaroxaban dose that will provide no more than that target value for the maximum, minimum, mean (arithmetic or geometric), median, average of the 3 highest values, or upper or lower boundary of the 90% confidence interval of the PK parameter (AUC_(inf) or C_(max)) in the patient population.

An exponential model was used to estimate the rivaroxaban redosing regimen. A formula was fitted to a large interval of rivaroxaban dosing data, encompassing doses from 5 mg to 80 mg, a 16-fold range. The resulting formula was then indexed to the actual AUC observed in the study and used to calculate an adjusted dose recommendation. In Tables 9-11 below, three targets of the exponential redosing AUC_(inf) (area under the curve extrapolated to infinity) were identified using AUC values corresponding to “A”, “B”, and “C” in FIG. 4 as discussed above, for subjects with mild renal impairment, and who are administered both rivaroxaban and verapamil (Table 9) or for patients with mild renal impairment treated only with rivaroxaban (Table 10). Table 11 shows corresponding re-dosing for patients with no renal impairment (“normal”) administered both rivaroxaban and verapamil.

The redosing shown below represents individual embodiments of the methods of the present invention. The value in the respective Dose 1, Dose 2, and Dose 3 columns is the maximum rivaroxaban dose that should be administered to a patient falling within the patient class defined in the header of the table, in order to provide a PK value (i.e., AUC or C_(max)) that does not exceed the corresponding Target 1, Target 2, or Target 3 PK parameter for the respective statistical parameter. By way of example, the calculated value of 8.7 mg rivaroxaban for the “maximum” Group, Dose 1 of Table 9 represents the maximum dose of rivaroxaban that should be administered to a patient with mild renal impairment, also treated with verapamil, to ensure that the highest (i.e., maximum) AUC_(inf) value obtained in that population would be no more than 3,792 μg·hr/L. Similarly, for treatment of a patient with mild renal impairment taking only rivaroxaban, to ensure that in a population of such patients, the AUC_(inf) of the upper boundary of the 90% confidence interval would not exceed 2,448 μg·hr/L, a dose of about 12.2 mg or rivaroxaban would be the highest dose that should be administered (Table 10, Group “90% CI, Upper Boundary”, Dose 3). Where the rivaroxaban dose is not listed in the table, the recommended dose of rivaroxaban (as defined by the Xarelto package insert revised August 2016) can be used.

Thus, in various embodiments, the present invention is directed to methods of treating a patient with a condition for which a Factor Xa inhibitor is indicated (selected from the group consisting of reducing the risk of stroke and systemic embolism in patients with non valvular atrial fibrillation, treating deep vein thrombosis (DVT), treating pulmonary embolism (PE), reducing the risk of DVT, and reducing the risk of PE, the prophylaxis of DVT which leads to PE in patients undergoing knee or hip replacement therapy), and a condition for which a calcium channel blocker is indicated (such as the management of essential hypertension), or any other condition disclosed herein, wherein said patient is administered verapamil and an amount of rivaroxaban such that the maximum, mean of the top 3, upper boundary of the 90% CI, median, arithmetic mean, geometric mean, lower boundary of the 90% CI, or minimum AUC or C_(max) is no more than about the Dose 1, Dose 2, or Dose 3 values (in mg) found in the respective portions of Tables 9, 11, 12, 14-16, 21, and 22. In various such embodiments, the patient has mild renal impairment. In other embodiments, the patient has normal renal function.

In various other embodiments, the present invention is directed to methods of treating a patient with a condition for which a Factor Xa inhibitor is indicated (selected from the group consisting of reducing the risk of stroke and systemic embolism in patients with non valvular atrial fibrillation, treating deep vein thrombosis (DVT), treating pulmonary embolism (PE), reducing the risk of DVT, and reducing the risk of PE, the prophylaxis of DVT which leads to PE in patients undergoing knee or hip replacement therapy), or any other condition disclosed herein, wherein said patient is administered an amount of rivaroxaban such that the maximum, mean of the top 3, upper boundary of the 90% CI, median, arithmetic mean, geometric mean, lower boundary of the 90% CI, or minimum AUC or C_(max) is no more than about the Dose 1, Dose 2, or Dose 3 values (in mg) found in the respective portions of Tables 10, 13, 17-19, and 23-26. In various such embodiments, the patient has mild renal impairment.

TABLE 9 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment treated with both rivaroxaban and verapamil using the exponential model. Mild Renal Impairment - R + V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 8.7 7.2 4.1 Mean of Top 3 3,792 3,404 2,448 9.3 7.7 4.4 90% CI, Upper 3,792 3,404 2,448 14.1 11.7 6.6 Boundary Median 3,792 3,404 2,448 19.3 16.0 9.1 Arithmetic Mean 3,792 3,404 2,448 17.3 14.4 8.1 Geometric Mean 3,792 3,404 2,448 18.5 15.3 8.7 90% CI, Lower 3,792 3,404 2,448 19.9 11.2 Boundary Minimum 3,792 3,404 2,448 16.4

TABLE 10 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment treated with a single dose of rivaroxaban using the exponential model. Mild Renal Impairment - R only Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 15.6 12.9 7.3 Mean of Top 3 3,792 3,404 2,448 17.8 14.8 8.4 90% CI, Upper 3,792 3,404 2,448 12.2 Boundary Median 3,792 3,404 2,448 17.0 Arithmetic Mean 3,792 3,404 2,448 15.5 Geometric Mean 3,792 3,404 2,448 17.1 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 11 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment treated with both rivaroxaban and verapamil using the exponential model. No Renal Impairment - R + V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 14.0 11.6 6.6 Mean of Top 3 3,792 3,404 2,448 17.1 14.2 8.0 90% CI, Upper 3,792 3,404 2,448 18.6 15.4 8.7 Boundary Median 3,792 3,404 2,448 16.9 9.5 Arithmetic Mean 3,792 3,404 2,448 18.4 10.4 Geometric Mean 3,792 3,404 2,448 19.1 10.8 90% CI, Lower 3,792 3,404 2,448 13.3 Boundary Minimum 3,792 3,404 2,448 19.8

A logarithmic model was also developed and used to estimate rivaroxaban redosing using the same observed-16 fold range. This was also indexed to the observed study data and used to calculate adjusted dose recommendations. In Tables [d]-[f] below, three targets of redosing based on AUC_(inf) were identified using AUC values corresponding to “A”, “B”, and “C” in FIG. 4 as discussed above, for subjects with mild renal impairment, and who are administered both rivaroxaban and verapamil (Table [d]) or for patients with mild renal impairment treated only with rivaroxaban (Table [e]). Table [f] shows corresponding re-dosing for patients with no renal impairment (“normal”) administered both rivaroxaban and verapamil.

TABLE 12 Redosing regimens of rivaroxaban in response to various target AUCs in subjects with mild renal impairment treated with both rivaroxaban and verapamil using the logarithmic model. Mild Renal Impairment - R + V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 9.5 8.7 6.9 Mean of Top 3 3,792 3,404 2,448 9.9 9.0 7.1 90% CI, Upper 3,792 3,404 2,448 12.8 11.3 8.3 Boundary Median 3,792 3,404 2,448 16.3 14.0 9.7 Arithmetic Mean 3,792 3,404 2,448 14.9 13.0 9.2 Geometric Mean 3,792 3,404 2,448 15.7 13.6 9.5 90% CI, Lower 3,792 3,404 2,448 19.7 16.7 11.0 Boundary Minimum 3,792 3,404 2,448 14.3

TABLE 13 Redosing regimens of rivaroxaban in response to various target AUCs in subjects with mild renal impairment treated with a single dose of rivaroxaban using the logarithmic model. Mild Renal Impairment - R only Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 13.8 12.1 8.7 Mean of Top 3 3,792 3,404 2,448 15.3 13.2 9.3 90% CI, Upper 3,792 3,404 2,448 17.9 11.6 Boundary Median 3,792 3,404 2,448 14.7 Arithmetic Mean 3,792 3,404 2,448 13.7 Geometric Mean 3,792 3,404 2,448 14.7 90% CI, Lower 3,792 3,404 2,448 17.5 Boundary Minimum 3,792 3,404 2,448

TABLE 14 Redosing regimens of rivaroxaban in response to various target AUCs in subjects with mild renal impairment treated with both rivaroxaban and verapamil using the logarithmic model. No Renal Impairment - R + V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 12.7 11.2 8.3 Mean of Top 3 3,792 3,404 2,448 14.8 12.9 9.2 90% CI, Upper 3,792 3,404 2,448 15.8 13.6 9.5 Boundary Median 3,792 3,404 2,448 17.0 14.6 10.0 Arithmetic Mean 3,792 3,404 2,448 18.4 15.7 10.5 Geometric Mean 3,792 3,404 2,448 19.0 16.1 10.8 90% CI, Lower 3,792 3,404 2,448 19.4 12.3 Boundary Minimum 3,792 3,404 2,448 16.6

Analogously to target AUC_(inf) values, three target C_(max) values were also used to calculate rivaroxaban redosing regimens (275, 268, and 317 ng/mL), respectively derived from the upper bound of the 90% confidence interval of the steady state C_(max) of patients administered 20 mg of rivaroxaban, the C_(max) for patients administered a single 10 mg dose of rivaroxaban in combination with a strong CYP3A4/Pgp inhibitor, and the upper boundary of the 90% confidence interval of the C_(max) level of subjects administered 20 mg rivaroxaban with food in study [11938] and applied to subjects with mild renal impairment treated with a single 20 mg dose of rivaroxaban alone, a single 20 mg dose of rivaroxaban and 360 mg verapamil, and for subjects with normal renal function on a single 20 mg dose of rivaroxaban and 360 mg verapamil. These redosing estimates are shown in Tables [e]-[l], below.

The fitted exponential C_(max) model indexed rivaroxaban redosing estimates are provided in Tables [e]-[h].

TABLE 15 Redosing regimens of rivaroxaban in response to various target single dose C_(max) in subjects with mild renal impairment treated with both rivaroxaban and verapamil using the exponential model. Mild Renal Impairment - R + V Exponential Redosing Single Dose C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 5.9 5.6 8.0 Mean of Top 3 275 268 317 9.8 9.3 13.4 90% CI, Upper 275 268 317 13.2 12.6 18.1 Boundary Median 275 268 317 17.2 16.3 Arithmetic Mean 275 268 317 17.4 16.5 Geometric Mean 275 268 317 18.9 18.0 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 16 Redosing regimens of rivaroxaban in response to various target steady state C_(max) in subjects with mild renal impairment treated with both rivaroxaban and Verapamil using the exponential model. Mild Renal Impairment - R + V Exponential Redosing Steady State C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 3.4 3.2 4.6 Mean of Top 3 275 268 317 5.6 5.4 7.7 90% CI, Upper 275 268 317 7.6 7.2 10.4 Boundary Median 275 268 317 9.9 9.4 13.5 Arithmetic Mean 275 268 317 10.0 9.5 13.7 Geometric Mean 275 268 317 10.9 10.4 14.9 90% CI, Lower 275 268 317 15.6 14.8 Boundary Minimum 275 268 317

TABLE 17 Redosing regimens of rivaroxaban in response to various target single dose C_(max) in subjects with mild renal impairment treated with a single dose of rivaroxaban using the exponential model. Mild Renal Impairment - R Only Exponential Redosing Single Dose C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 6.2 5.9 8.4 Mean of Top 3 275 268 317 9.5 9.0 13.0 90% CI, Upper 275 268 317 15.9 15.1 Boundary Median 275 268 317 Arithmetic Mean 275 268 317 19.9 18.9 Geometric Mean 275 268 317 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 18 Redosing regimens of rivaroxaban in response to various target steady state C_(max) in subjects with mild renal impairment treated with a single dose of rivaroxaban using the exponential model. Mild Renal Impairment - R Only Exponential Redosing Steady State C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 4.0 3.8 5.5 Mean of Top 3 275 268 317 6.2 5.9 8.4 90% CI, Upper 275 268 317 10.4 9.8 14.1 Boundary Median 275 268 317 15.8 15.0 Arithmetic 275 268 317 12.9 12.3 17.6 Mean Geometric 275 268 317 14.2 13.5 19.4 Mean 90% CI, Lower 275 268 317 18.6 17.7 Boundary Minimum 275 268 317

TABLE 19 Redosing regimens of rivaroxaban in response to various target single dose C_(max) in subjects with no renal impairment treated with both rivaroxaban and verapamil using the exponential model. No Renal Impairment - R Only Exponential Redosing Single Dose C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 8.1 7.7 11.1 Mean of Top 3 275 268 317 10.3 9.7 14.0 90% CI, Upper 275 268 317 12.1 11.5 16.5 Boundary Median 275 268 317 16.3 15.5 Arithmetic 275 268 317 16.0 15.2 Mean Geometric 275 268 317 17.3 16.4 Mean 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 20 Redosing regimens of rivaroxaban in response to various target steady state C_(max) in subjects with no renal impairment treated with both rivaroxaban and verapamil using the exponential model. No Renal Impairment - R Only Exponential Redosing Steady State C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 5.9 5.6 8.1 Mean of Top 3 275 268 317 7.4 7.1 10.2 90% CI, Upper 275 268 317 8.8 8.3 12.0 Boundary Median 275 268 317 11.9 11.3 16.2 Arithmetic 275 268 317 11.6 11.0 15.8 Mean Geometric 275 268 317 12.5 11.9 17.1 Mean 90% CI, Lower 275 268 317 17.9 17.0 Boundary Minimum 275 268 317

The fitted logarithmic model rivaroxaban redosing regimen indexed results are shown in Tables [d]-[f] and [m]-[r], herein.

TABLE 21 Redosing regimens of rivaroxaban in response to various target single dose C_(max) in subjects with mild renal impairment treated with both rivaroxaban and verapamil using the logarithmic model. Mild Renal Impairment - R + V Logarithmic Redosing Single Dose C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 7.4 7.3 8.8 Mean of Top 3 275 268 317 10.0 9.7 12.4 90% CI, Upper 275 268 317 12.3 11.8 15.8 Boundary Median 275 268 317 15.1 14.5 Arithmetic 275 268 317 15.2 14.6 Mean Geometric 275 268 317 16.4 15.7 Mean 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 22 Redosing regimens of rivaroxaban in response to various target steady state C_(max) in subjects with mild renal impairment treated with both rivaroxaban and verapamil using the logarithmic model. Mild Renal Impairment - R + V Logarithmic Redosing Steady State C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 5.8 5.7 6.6 Mean of Top 3 275 268 317 7.3 7.1 8.6 90% CI, Upper 275 268 317 8.6 8.3 10.4 Boundary Median 275 268 317 10.1 9.7 12.5 Arithmetic 275 268 317 10.1 9.8 12.6 Mean Geometric 275 268 317 10.7 10.4 13.5 Mean 90% CI, Lower 275 268 317 14.0 13.4 18.3 Boundary Minimum 275 268 317

TABLE 23 Redosing regimens of rivaroxaban in response to various target single dose C_(max) in subjects with mild renal impairment treated with a single dose of rivaroxaban using the logarithmic model. Mild Renal Impairment - R Only Logarithmic Redosing Single Dose C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 7.6 7.4 9.1 Mean of Top 3 275 268 317 9.8 9.5 12.1 90% CI, Upper 275 268 317 14.2 13.6 18.6 Boundary Median 275 268 317 19.6 Arithmetic 275 268 317 17.1 16.4 Mean Geometric 275 268 317 18.7 17.8 Mean 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 24 Redosing regimens of rivaroxaban in response to various target steady state C_(max) in subjects with mild renal impairment treated with a single dose of rivaroxaban using the logarithmic model. Mild Renal Impairment - R Only Logarithmic Redosing Steady State C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 6.2 6.1 7.2 Mean of Top 3 275 268 317 7.6 7.4 9.1 90% CI, Upper 275 268 317 10.4 10.0 12.9 Boundary Median 275 268 317 14.1 13.5 18.4 Arithmetic 275 268 317 12.1 11.6 15.4 Mean Geometric 275 268 317 13.0 12.5 16.8 Mean 90% CI, Lower 275 268 317 16.2 15.5 Boundary Minimum 275 268 317

TABLE 25 Redosing regimens of rivaroxaban in response to various target single dose C_(max) in subjects with no renal impairment treated with both rivaroxaban and verapamil using the logarithmic model. No Renal Impairment - R Only Logarithmic Redosing Single Dose C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 8.9 8.6 10.9 Mean of Top 3 275 268 317 10.3 9.9 12.8 90% CI, Upper 275 268 317 11.5 11.1 14.6 Boundary Median 275 268 317 14.5 13.9 19.0 Arithmetic 275 268 317 14.2 13.7 18.7 Mean Geometric 275 268 317 15.1 14.5 Mean 90% CI, Lower 275 268 317 19.9 Boundary Minimum 275 268 317

TABLE 26 Redosing regimens of rivaroxaban in response to various target steady state C_(max) in subjects with no renal impairment treated with both rivaroxaban and verapamil using the logarithmic model. No Renal Impairment - R Only Logarithmic Redosing Steady State C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 7.5 7.3 8.9 Mean of Top 3 275 268 317 8.5 8.2 10.2 90% CI, Upper 275 268 317 9.3 9.0 11.4 Boundary Median 275 268 317 11.4 10.9 14.4 Arithmetic 275 268 317 11.2 10.8 14.1 Mean Geometric 275 268 317 11.8 11.4 15.0 Mean 90% CI, Lower 275 268 317 15.6 15.0 Boundary Minimum 275 268 317

Example 5—PBPK Model for Extending Clinical Findings and Determining Redosing Levels of Rivaroxaban to Reduce the Risk of Major Bleeding

A Physiologically based Pharmacokinetic (PBPK) model was developed using the data from the previously mentioned clinical studies to confirm and extend the key findings. Specifically, once fully developed the model was used to determine from multiple simulations ranges of AUC and Cmax for normal, mild renal impairment and moderate renal impairment subjects on rivaroxaban alone and on rivaroxaban and verapamil at steady state. The model was also used to test how these groups would react at verapamil doses ranging from 0 mg to 360 mg inclusively. These AUC and Cmax values were used to calculate redosing levels based on the exponential and logarithmic methods described herein.

Each of the rivaroxaban redosing values specified in the following tables is an embodiment of the methods of the present invention, wherein a patient having the specified renal status, and concomitantly (or not as indicated) administered verapamil, and who would be administered the specified recommended rivaroxaban dose, may be re-dosed at the indicated level (or to a level rounded to the nearest mg or 0.5 mg).

TABLE 27 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, no concomitant verapamil, using the exponential model. No Renal Impairment - 15 mg Recommended R, 0 V Exponential Redosing AUC Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 3,792 3,404 2,448 8.7 90% CI, Upper 3,792 3,404 2,448 Boundary 80% CI, Upper 3,792 3,404 2,448 Boundary IQR Upper 3,792 3,404 2,448 Median 3,792 3,404 2,448 Arithmetic 3,792 3,404 2,448 Mean Geometric 3,792 3,404 2,448 Mean IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 28 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, 120 mg concomitant verapamil, using the exponential model. No Renal Impairment - 15 mg Recommended R, 120 V Exponential Redosing AUC Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 3,792 3,404 2,448 11.9 9.9 5.6 90% CI, Upper 3,792 3,404 2,448 9.8 Boundary 80% CI, Upper 3,792 3,404 2,448 10.9 Boundary IQR Upper 3,792 3,404 2,448 12.6 Median 3,792 3,404 2,448 Arithmetic 3,792 3,404 2,448 14.9 Mean Geometric 3,792 3,404 2,448 Mean IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 29 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, 240 mg concomitant verapamil, using the exponential model. No Renal Impairment - 15 mg Recommended R, 240 V Exponential Redosing AUC Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 3,792 3,404 2,448 10.9 9.0 5.1 90% CI, Upper 3,792 3,404 2,448 8.9 Boundary 80% CI, Upper 3,792 3,404 2,448 9.8 Boundary IQR Upper 3,792 3,404 2,448 11.4 Median 3,792 3,404 2,448 13.8 Arithmetic 3,792 3,404 2,448 13.5 Mean Geometric 3,792 3,404 2,448 13.8 Mean IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 30 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, 360 mg concomitant verapamil, using the exponential model. No Renal Impairment - 15 mg Recommended R, 360 V Exponential Redosing AUC Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 3,792 3,404 2,448 10.3 8.5 4.8 90% CI, Upper 3,792 3,404 2,448 14.6 8.3 Boundary 80% CI, Upper 3,792 3,404 2,448 9.1 Boundary IQR Upper 3,792 3,404 2,448 10.7 Median 3,792 3,404 2,448 12.9 Arithmetic 3,792 3,404 2,448 12.6 Mean Geometric 3,792 3,404 2,448 12.9 Mean IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 31 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, no concomitant verapamil, using the exponential model. No Renal Impairment - 20 mg Recommended R, 0 V Exponential Redosing AUC Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 3,792 3,404 2,448 14.3 11.9 6.7 90% CI, Upper 3,792 3,404 2,448 12.1 Boundary 80% CI, Upper 3,792 3,404 2,448 13.4 Boundary IQR Upper 3,792 3,404 2,448 15.7 Median 3,792 3,404 2,448 19.2 Arithmetic 3,792 3,404 2,448 18.9 Mean Geometric 3,792 3,404 2,448 19.4 Mean IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 32 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, 120 mg concomitant verapamil, using the exponential model. No Renal Impairment - 20 mg Recommended R, 120 V Exponential Redosing AUC Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 3,792 3,404 2,448 9.1 7.6 4.3 90% CI, Upper 3,792 3,404 2,448 16.1 13.3 7.5 Boundary 80% CI, Upper 3,792 3,404 2,448 17.8 14.8 8.4 Boundary IQR Upper 3,792 3,404 2,448 17.1 9.7 Median 3,792 3,404 2,448 11.7 Arithmetic 3,792 3,404 2,448 11.5 Mean Geometric 3,792 3,404 2,448 11.7 Mean IQR Lower 3,792 3,404 2,448 14.1 80% CI, Lower 3,792 3,404 2,448 16.8 Boundary 90% CI, Lower 3,792 3,404 2,448 18.8 Boundary Minimum 3,792 3,404 2,448

TABLE 33 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the exponential model. No Renal Impairment - 20 mg Recommended R, 240 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 8.4 6.9 3.9 90% CI, Upper 3,792 3,404 2,448 14.5 12.0 6.8 Boundary 80% CI, Upper 3,792 3,404 2,448 16.0 13.3 7.5 Boundary IQR Upper 3,792 3,404 2,448 18.6 15.5 8.7 Median 3,792 3,404 2,448 18.7 10.6 Arithmetic Mean 3,792 3,404 2,448 18.3 10.4 Geometric Mean 3,792 3,404 2,448 18.8 10.6 IQR Lower 3,792 3,404 2,448 12.8 80% CI, Lower 3,792 3,404 2,448 15.2 Boundary 90% CI, Lower 3,792 3,404 2,448 17.1 Boundary Minimum 3,792 3,404 2,448

TABLE 34 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, 360 mg concomitant verapamil, using the exponential model. No Renal Impairment - 20 mg Recommended R, 360 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 7.9 6.6 3.7 90% CI, Upper 3,792 3,404 2,448 13.6 11.2 6.4 Boundary 80% CI, Upper 3,792 3,404 2,448 14.9 12.4 7.0 Boundary IQR Upper 3,792 3,404 2,448 17.5 14.5 8.2 Median 3,792 3,404 2,448 17.6 9.9 Arithmetic Mean 3,792 3,404 2,448 17.1 9.7 Geometric Mean 3,792 3,404 2,448 17.6 9.9 IQR Lower 3,792 3,404 2,448 11.9 80% CI, Lower 3,792 3,404 2,448 14.2 Boundary 90% CI, Lower 3,792 3,404 2,448 16.2 Boundary Minimum 3,792 3,404 2,448

TABLE 35 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, no concomitant verapamil, using the exponential model. Mild Renal Impairment - 15 mg Recommended R, 0 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 8.8 90% CI, Upper 3,792 3,404 2,448 14.2 Boundary 80% CI, Upper 3,792 3,404 2,448 Boundary IQR Upper 3,792 3,404 2,448 Median 3,792 3,404 2,448 Arithmetic Mean 3,792 3,404 2,448 Geometric Mean 3,792 3,404 2,448 IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 36 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, 120 mg concomitant verapamil, using the exponential model. Mild Renal Impairment - 15 mg Recommended R, 120 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 12.4 10.3 5.8 90% CI, Upper 3,792 3,404 2,448 8.6 Boundary 80% CI, Upper 3,792 3,404 2,448 9.4 Boundary IQR Upper 3,792 3,404 2,448 11.3 Median 3,792 3,404 2,448 13.8 Arithmetic Mean 3,792 3,404 2,448 13.4 Geometric Mean 3,792 3,404 2,448 13.8 IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 37 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, 240 mg concomitant verapamil, using the exponential model. Mild Renal Impairment - 15 mg Recommended R, 240 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 11.0 9.1 5.2 90% CI, Upper 3,792 3,404 2,448 13.6 7.7 Boundary 80% CI, Upper 3,792 3,404 2,448 8.5 Boundary IQR Upper 3,792 3,404 2,448 10.2 Median 3,792 3,404 2,448 12.5 Arithmetic Mean 3,792 3,404 2,448 12.2 Geometric Mean 3,792 3,404 2,448 12.5 IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 38 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, 360 mg concomitant verapamil, using the exponential model. Mild Renal Impairment - 15 mg Recommended R, 360 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 10.1 8.4 4.7 90% CI, Upper 3,792 3,404 2,448 12.8 7.2 Boundary 80% CI, Upper 3,792 3,404 2,448 14.1 8.0 Boundary IQR Upper 3,792 3,404 2,448 9.5 Median 3,792 3,404 2,448 11.7 Arithmetic Mean 3,792 3,404 2,448 11.4 Geometric Mean 3,792 3,404 2,448 11.7 IQR Lower 3,792 3,404 2,448 14.2 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 39 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, no concomitant verapamil, using the exponential model. Mild Renal Impairment - 20 mg Recommended R, 0 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 14.4 12.0 6.8 90% CI, Upper 3,792 3,404 2,448 19.2 10.9 Boundary 80% CI, Upper 3,792 3,404 2,448 12.0 Boundary IQR Upper 3,792 3,404 2,448 14.7 Median 3,792 3,404 2,448 17.8 Arithmetic Mean 3,792 3,404 2,448 17.4 Geometric Mean 3,792 3,404 2,448 17.9 IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 40 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, 120 mg concomitant verapamil, using the exponential model. Mild Renal Impairment - 20 mg Recommended R, 120 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 9.5 7.9 4.5 90% CI, Upper 3,792 3,404 2,448 14.0 11.6 6.6 Boundary 80% CI, Upper 3,792 3,404 2,448 15.5 12.8 7.3 Boundary IQR Upper 3,792 3,404 2,448 18.5 15.3 8.7 Median 3,792 3,404 2,448 18.7 10.6 Arithmetic Mean 3,792 3,404 2,448 18.3 10.3 Geometric Mean 3,792 3,404 2,448 18.7 10.6 IQR Lower 3,792 3,404 2,448 12.9 80% CI, Lower 3,792 3,404 2,448 15.7 Boundary 90% CI, Lower 3,792 3,404 2,448 17.6 Boundary Minimum 3,792 3,404 2,448

TABLE 41 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the exponential model. Mild Renal Impairment - 20 mg Recommended R, 240 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 8.5 7.0 4.0 90% CI, Upper 3,792 3,404 2,448 12.6 10.4 5.9 Boundary 80% CI, Upper 3,792 3,404 2,448 14.0 11.6 6.6 Boundary IQR Upper 3,792 3,404 2,448 16.6 13.8 7.8 Median 3,792 3,404 2,448 16.9 9.6 Arithmetic Mean 3,792 3,404 2,448 19.9 16.5 9.3 Geometric Mean 3,792 3,404 2,448 16.9 9.6 IQR Lower 3,792 3,404 2,448 11.7 80% CI, Lower 3,792 3,404 2,448 14.2 Boundary 90% CI, Lower 3,792 3,404 2,448 16.0 Boundary Minimum 3,792 3,404 2,448

TABLE 42 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the exponential model. Mild Renal Impairment - 20 mg Recommended R, 360 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 7.8 6.4 3.6 90% CI, Upper 3,792 3,404 2,448 11.9 9.8 5.6 Boundary 80% CI, Upper 3,792 3,404 2,448 13.1 10.8 6.1 Boundary IQR Upper 3,792 3,404 2,448 15.6 13.0 7.3 Median 3,792 3,404 2,448 19.1 15.8 9.0 Arithmetic Mean 3,792 3,404 2,448 18.7 15.5 8.8 Geometric Mean 3,792 3,404 2,448 19.1 15.9 9.0 IQR Lower 3,792 3,404 2,448 19.4 11.0 80% CI, Lower 3,792 3,404 2,448 13.3 Boundary 90% CI, Lower 3,792 3,404 2,448 15.1 Boundary Minimum 3,792 3,404 2,448

TABLE 43 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, no concomitant verapamil, using the exponential model. Moderate Renal Impairment - 15 mg Recommended R, 0 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 14.1 8.0 90% CI, Upper 3,792 3,404 2,448 12.6 Boundary 80% CI, Upper 3,792 3,404 2,448 14.3 Boundary IQR Upper 3,792 3,404 2,448 Median 3,792 3,404 2,448 Arithmetic Mean 3,792 3,404 2,448 Geometric Mean 3,792 3,404 2,448 IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 44 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, 120 mg concomitant verapamil, using the exponential model. Moderate Renal Impairment - 15 mg Recommended R, 120 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 9.7 8.1 4.6 90% CI, Upper 3,792 3,404 2,448 13.1 7.4 Boundary 80% CI, Upper 3,792 3,404 2,448 14.9 8.4 Boundary IQR Upper 3,792 3,404 2,448 10.1 Median 3,792 3,404 2,448 12.3 Arithmetic Mean 3,792 3,404 2,448 12.0 Geometric Mean 3,792 3,404 2,448 12.4 IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 45 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, 240 mg concomitant verapamil, using the exponential model. Moderate Renal Impairment - 15 mg Recommended R, 240 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 8.7 7.2 4.1 90% CI, Upper 3,792 3,404 2,448 14.3 11.8 6.7 Boundary 80% CI, Upper 3,792 3,404 2,448 13.5 7.6 Boundary IQR Upper 3,792 3,404 2,448 9.2 Median 3,792 3,404 2,448 11.2 Arithmetic Mean 3,792 3,404 2,448 10.9 Geometric Mean 3,792 3,404 2,448 11.2 IQR Lower 3,792 3,404 2,448 13.8 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 46 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, 360 mg concomitant verapamil, using the exponential model. Moderate Renal Impairment - 15 mg Recommended R, 360 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 8.1 6.7 3.8 90% CI, Upper 3,792 3,404 2,448 13.4 11.1 6.3 Boundary 80% CI, Upper 3,792 3,404 2,448 12.6 7.1 Boundary IQR Upper 3,792 3,404 2,448 8.6 Median 3,792 3,404 2,448 10.5 Arithmetic Mean 3,792 3,404 2,448 10.3 Geometric Mean 3,792 3,404 2,448 10.6 IQR Lower 3,792 3,404 2,448 13.0 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 47 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, no concomitant verapamil, using the exponential model. Moderate Renal Impairment - 20 mg Recommended R, 0 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 13.1 10.9 6.1 90% CI, Upper 3,792 3,404 2,448 17.0 9.6 Boundary 80% CI, Upper 3,792 3,404 2,448 19.4 11.0 Boundary IQR Upper 3,792 3,404 2,448 13.1 Median 3,792 3,404 2,448 16.1 Arithmetic Mean 3,792 3,404 2,448 15.8 Geometric Mean 3,792 3,404 2,448 16.3 IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 48 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, 120 mg concomitant verapamil, using the exponential model. Moderate Renal Impairment - 20 mg Recommended R, 120 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 7.5 6.2 3.5 90% CI, Upper 3,792 3,404 2,448 12.1 10.1 5.7 Boundary 80% CI, Upper 3,792 3,404 2,448 13.8 11.5 6.5 Boundary IQR Upper 3,792 3,404 2,448 16.6 13.8 7.8 Median 3,792 3,404 2,448 16.7 9.5 Arithmetic Mean 3,792 3,404 2,448 19.7 16.4 9.3 Geometric Mean 3,792 3,404 2,448 16.8 9.5 IQR Lower 3,792 3,404 2,448 11.7 80% CI, Lower 3,792 3,404 2,448 14.0 Boundary 90% CI, Lower 3,792 3,404 2,448 15.7 Boundary Minimum 3,792 3,404 2,448

TABLE 49 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the exponential model. Moderate Renal Impairment - 20 mg Recommended R, 240 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 6.7 5.6 3.1 90% CI, Upper 3,792 3,404 2,448 11.0 9.1 5.1 Boundary 80% CI, Upper 3,792 3,404 2,448 12.5 10.3 5.9 Boundary IQR Upper 3,792 3,404 2,448 15.0 12.5 7.1 Median 3,792 3,404 2,448 18.3 15.2 8.6 Arithmetic Mean 3,792 3,404 2,448 17.9 14.8 8.4 Geometric Mean 3,792 3,404 2,448 18.4 15.3 8.6 IQR Lower 3,792 3,404 2,448 18.7 10.6 80% CI, Lower 3,792 3,404 2,448 12.8 Boundary 90% CI, Lower 3,792 3,404 2,448 14.3 Boundary Minimum 3,792 3,404 2,448

TABLE 50 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, 360 mg concomitant verapamil, using the exponential model. Moderate Renal Impairment - 20 mg Recommended R, 360 V Exponential Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 6.2 5.2 2.9 90% CI, Upper 3,792 3,404 2,448 10.3 8.5 4.8 Boundary 80% CI, Upper 3,792 3,404 2,448 11.6 9.6 5.5 Boundary IQR Upper 3,792 3,404 2,448 14.1 11.7 6.6 Median 3,792 3,404 2,448 17.2 14.3 8.1 Arithmetic Mean 3,792 3,404 2,448 16.8 14.0 7.9 Geometric Mean 3,792 3,404 2,448 17.3 14.3 8.1 IQR Lower 3,792 3,404 2,448 17.7 10.0 80% CI, Lower 3,792 3,404 2,448 12.0 Boundary 90% CI, Lower 3,792 3,404 2,448 13.5 Boundary Minimum 3,792 3,404 2,448

TABLE 51 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, no concomitant verapamil, using the logarithmic model. No Renal Impairment - 15 mg Recommended R, 0 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 14.4 10.4 90% CI, Upper 3,792 3,404 2,448 14.6 Boundary 80% CI, Upper 3,792 3,404 2,448 Boundary IQR Upper 3,792 3,404 2,448 Median 3,792 3,404 2,448 Arithmetic Mean 3,792 3,404 2,448 Geometric Mean 3,792 3,404 2,448 IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 52 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, 120 mg concomitant verapamil, using the logarithmic model. No Renal Impairment - 15 mg Recommended R, 120 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 12.4 11.1 8.0 90% CI, Upper 3,792 3,404 2,448 11.1 Boundary 80% CI, Upper 3,792 3,404 2,448 11.7 Boundary IQR Upper 3,792 3,404 2,448 12.8 Median 3,792 3,404 2,448 14.3 Arithmetic Mean 3,792 3,404 2,448 14.1 Geometric Mean 3,792 3,404 2,448 14.3 IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 53 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, 240 mg concomitant verapamil, using the logarithmic model. No Renal Impairment - 15 mg Recommended R, 240 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 11.8 10.6 7.6 90% CI, Upper 3,792 3,404 2,448 14.5 10.4 Boundary 80% CI, Upper 3,792 3,404 2,448 11.0 Boundary IQR Upper 3,792 3,404 2,448 12.1 Median 3,792 3,404 2,448 13.5 Arithmetic Mean 3,792 3,404 2,448 13.3 Geometric Mean 3,792 3,404 2,448 13.5 IQR Lower 3,792 3,404 2,448 15.0 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 54 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, 360 mg concomitant verapamil, using the logarithmic model. No Renal Impairment - 15 mg Recommended R, 360 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 11.4 10.2 7.3 90% CI, Upper 3,792 3,404 2,448 13.9 10.0 Boundary 80% CI, Upper 3,792 3,404 2,448 14.8 10.6 Boundary IQR Upper 3,792 3,404 2,448 11.6 Median 3,792 3,404 2,448 13.0 Arithmetic Mean 3,792 3,404 2,448 12.8 Geometric Mean 3,792 3,404 2,448 13.0 IQR Lower 3,792 3,404 2,448 14.4 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 55 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, no concomitant verapamil, using the logarithmic model. No Renal Impairment - 20 mg Recommended R, 0 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 16.0 14.4 10.4 90% CI, Upper 3,792 3,404 2,448 14.6 Boundary 80% CI, Upper 3,792 3,404 2,448 15.5 Boundary IQR Upper 3,792 3,404 2,448 16.9 Median 3,792 3,404 2,448 19.0 Arithmetic Mean 3,792 3,404 2,448 18.8 Geometric Mean 3,792 3,404 2,448 19.1 IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 56 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, 120 mg concomitant verapamil, using the logarithmic model. No Renal Impairment - 20 mg Recommended R, 120 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 12.4 11.1 8.0 90% CI, Upper 3,792 3,404 2,448 17.1 15.4 11.1 Boundary 80% CI, Upper 3,792 3,404 2,448 18.2 16.3 11.7 Boundary IQR Upper 3,792 3,404 2,448 19.8 17.8 12.8 Median 3,792 3,404 2,448 19.9 14.3 Arithmetic Mean 3,792 3,404 2,448 19.6 14.1 Geometric Mean 3,792 3,404 2,448 19.9 14.3 IQR Lower 3,792 3,404 2,448 15.9 80% CI, Lower 3,792 3,404 2,448 17.6 Boundary 90% CI, Lower 3,792 3,404 2,448 18.8 Boundary Minimum 3,792 3,404 2,448

TABLE 57 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the logarithmic model. No Renal Impairment - 20 mg Recommended R, 240 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 11.8 10.6 7.6 90% CI, Upper 3,792 3,404 2,448 16.1 14.5 10.4 Boundary 80% CI, Upper 3,792 3,404 2,448 17.1 15.3 11.0 Boundary IQR Upper 3,792 3,404 2,448 18.7 16.8 12.1 Median 3,792 3,404 2,448 18.7 13.5 Arithmetic Mean 3,792 3,404 2,448 18.5 13.3 Geometric Mean 3,792 3,404 2,448 18.8 13.5 IQR Lower 3,792 3,404 2,448 15.0 80% CI, Lower 3,792 3,404 2,448 16.6 Boundary 90% CI, Lower 3,792 3,404 2,448 17.8 Boundary Minimum 3,792 3,404 2,448

TABLE 58 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, 360 mg concomitant verapamil, using the logarithmic model. No Renal Impairment - 20 mg Recommended R, 360 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 11.4 10.2 7.3 90% CI, Upper 3,792 3,404 2,448 15.5 13.9 10.0 Boundary 80% CI, Upper 3,792 3,404 2,448 16.4 14.8 10.6 Boundary IQR Upper 3,792 3,404 2,448 18.0 16.2 11.6 Median 3,792 3,404 2,448 18.0 13.0 Arithmetic Mean 3,792 3,404 2,448 19.8 17.8 12.8 Geometric Mean 3,792 3,404 2,448 18.0 13.0 IQR Lower 3,792 3,404 2,448 14.4 80% CI, Lower 3,792 3,404 2,448 16.0 Boundary 90% CI, Lower 3,792 3,404 2,448 17.2 Boundary Minimum 3,792 3,404 2,448

TABLE 59 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, no concomitant verapamil, using the logarithmic model. Mild Renal Impairment - 15 mg Recommended R, 0 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 14.5 10.4 90% CI, Upper 3,792 3,404 2,448 13.7 Boundary 80% CI, Upper 3,792 3,404 2,448 14.5 Boundary IQR Upper 3,792 3,404 2,448 Median 3,792 3,404 2,448 Arithmetic Mean 3,792 3,404 2,448 Geometric Mean 3,792 3,404 2,448 IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 60 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, 120 mg concomitant verapamil, using the logarithmic model. Mild Renal Impairment - 15 mg Recommended R, 120 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 12.7 11.4 8.2 90% CI, Upper 3,792 3,404 2,448 14.2 10.2 Boundary 80% CI, Upper 3,792 3,404 2,448 10.8 Boundary IQR Upper 3,792 3,404 2,448 12.0 Median 3,792 3,404 2,448 13.5 Arithmetic Mean 3,792 3,404 2,448 13.3 Geometric Mean 3,792 3,404 2,448 13.5 IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 61 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, 240 mg concomitant verapamil, using the logarithmic model. Mild Renal Impairment - 15 mg Recommended R, 240 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 11.8 10.6 7.6 90% CI, Upper 3,792 3,404 2,448 14.9 13.3 9.6 Boundary 80% CI, Upper 3,792 3,404 2,448 14.2 10.2 Boundary IQR Upper 3,792 3,404 2,448 11.3 Median 3,792 3,404 2,448 12.7 Arithmetic Mean 3,792 3,404 2,448 12.5 Geometric Mean 3,792 3,404 2,448 12.7 IQR Lower 3,792 3,404 2,448 14.2 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 62 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, 360 mg concomitant verapamil, using the logarithmic model. Mild Renal Impairment - 15 mg Recommended R, 360 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 11.3 10.1 7.3 90% CI, Upper 3,792 3,404 2,448 14.4 12.9 9.3 Boundary 80% CI, Upper 3,792 3,404 2,448 13.7 9.8 Boundary IQR Upper 3,792 3,404 2,448 10.9 Median 3,792 3,404 2,448 12.2 Arithmetic Mean 3,792 3,404 2,448 12.1 Geometric Mean 3,792 3,404 2,448 12.2 IQR Lower 3,792 3,404 2,448 13.7 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 63 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, no concomitant verapamil, using the logarithmic model. Mild Renal Impairment - 20 mg Recommended R, 0 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 16.1 14.5 10.4 90% CI, Upper 3,792 3,404 2,448 19.0 13.7 Boundary 80% CI, Upper 3,792 3,404 2,448 14.5 Boundary IQR Upper 3,792 3,404 2,448 16.3 Median 3,792 3,404 2,448 18.2 Arithmetic Mean 3,792 3,404 2,448 18.0 Geometric Mean 3,792 3,404 2,448 18.3 IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 64 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, 120 mg concomitant verapamil, using the logarithmic model. Mild Renal Impairment - 20 mg Recommended R, 120 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 12.7 11.4 8.2 90% CI, Upper 3,792 3,404 2,448 15.8 14.2 10.2 Boundary 80% CI, Upper 3,792 3,404 2,448 16.8 15.1 10.8 Boundary IQR Upper 3,792 3,404 2,448 18.6 16.7 12.0 Median 3,792 3,404 2,448 18.7 13.5 Arithmetic Mean 3,792 3,404 2,448 18.5 13.3 Geometric Mean 3,792 3,404 2,448 18.7 13.5 IQR Lower 3,792 3,404 2,448 15.1 80% CI, Lower 3,792 3,404 2,448 16.9 Boundary 90% CI, Lower 3,792 3,404 2,448 18.1 Boundary Minimum 3,792 3,404 2,448

TABLE 65 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the logarithmic model. Mild Renal Impairment - 20 mg Recommended R, 240 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 11.8 10.6 7.6 90% CI, Upper 3,792 3,404 2,448 14.9 13.3 9.6 Boundary 80% CI, Upper 3,792 3,404 2,448 15.8 14.2 10.2 Boundary IQR Upper 3,792 3,404 2,448 17.5 15.7 11.3 Median 3,792 3,404 2,448 19.7 17.7 12.7 Arithmetic Mean 3,792 3,404 2,448 19.4 17.4 12.5 Geometric Mean 3,792 3,404 2,448 19.7 17.7 12.7 IQR Lower 3,792 3,404 2,448 19.8 14.2 80% CI, Lower 3,792 3,404 2,448 15.9 Boundary 90% CI, Lower 3,792 3,404 2,448 17.1 Boundary Minimum 3,792 3,404 2,448

TABLE 66 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the logarithmic model. Mild Renal Impairment - 20 mg Recommended R, 360 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 11.3 10.1 7.3 90% CI, Upper 3,792 3,404 2,448 14.4 12.9 9.3 Boundary 80% CI, Upper 3,792 3,404 2,448 15.2 13.7 9.8 Boundary IQR Upper 3,792 3,404 2,448 16.9 15.1 10.9 Median 3,792 3,404 2,448 18.9 17.0 12.2 Arithmetic Mean 3,792 3,404 2,448 18.7 16.8 12.1 Geometric Mean 3,792 3,404 2,448 19.0 17.0 12.2 IQR Lower 3,792 3,404 2,448 19.1 13.7 80% CI, Lower 3,792 3,404 2,448 15.4 Boundary 90% CI, Lower 3,792 3,404 2,448 16.5 Boundary Minimum 3,792 3,404 2,448

TABLE 67 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, no concomitant verapamil, using the logarithmic model. Moderate Renal Impairment - 15 mg Recommended R, 0 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 13.7 9.8 90% CI, Upper 3,792 3,404 2,448 12.8 Boundary 80% CI, Upper 3,792 3,404 2,448 13.8 Boundary IQR Upper 3,792 3,404 2,448 Median 3,792 3,404 2,448 Arithmetic Mean 3,792 3,404 2,448 Geometric Mean 3,792 3,404 2,448 IQR Lower 3,792 3,404 2,448 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 68 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, 120 mg concomitant verapamil, using the logarithmic model. Moderate Renal Impairment - 15 mg Recommended R, 120 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 11.0 9.9 7.1 90% CI, Upper 3,792 3,404 2,448 14.6 13.1 9.4 Boundary 80% CI, Upper 3,792 3,404 2,448 14.1 10.1 Boundary IQR Upper 3,792 3,404 2,448 11.3 Median 3,792 3,404 2,448 12.6 Arithmetic Mean 3,792 3,404 2,448 12.5 Geometric Mean 3,792 3,404 2,448 12.7 IQR Lower 3,792 3,404 2,448 14.2 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 69 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, 240 mg concomitant verapamil, using the logarithmic model. Moderate Renal Impairment - 15 mg Recommended R, 240 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 10.3 9.3 6.7 90% CI, Upper 3,792 3,404 2,448 13.7 12.3 8.9 Boundary 80% CI, Upper 3,792 3,404 2,448 14.8 13.3 9.6 Boundary IQR Upper 3,792 3,404 2,448 14.8 10.6 Median 3,792 3,404 2,448 11.9 Arithmetic Mean 3,792 3,404 2,448 11.8 Geometric Mean 3,792 3,404 2,448 12.0 IQR Lower 3,792 3,404 2,448 13.5 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 70 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, 360 mg concomitant verapamil, using the logarithmic model. Moderate Renal Impairment - 15 mg Recommended R, 360 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 9.9 8.9 6.4 90% CI, Upper 3,792 3,404 2,448 13.2 11.9 8.5 Boundary 80% CI, Upper 3,792 3,404 2,448 14.2 12.8 9.2 Boundary IQR Upper 3,792 3,404 2,448 14.3 10.3 Median 3,792 3,404 2,448 11.5 Arithmetic Mean 3,792 3,404 2,448 11.4 Geometric Mean 3,792 3,404 2,448 11.5 IQR Lower 3,792 3,404 2,448 13.0 80% CI, Lower 3,792 3,404 2,448 14.5 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 71 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, no concomitant verapamil, using the logarithmic model. Moderate Renal Impairment - 20 mg Recommended R, 0 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 15.2 13.7 9.8 90% CI, Upper 3,792 3,404 2,448 19.8 17.7 12.8 Boundary 80% CI, Upper 3,792 3,404 2,448 19.1 13.8 Boundary IQR Upper 3,792 3,404 2,448 15.2 Median 3,792 3,404 2,448 17.2 Arithmetic Mean 3,792 3,404 2,448 17.0 Geometric Mean 3,792 3,404 2,448 17.3 IQR Lower 3,792 3,404 2,448 19.6 80% CI, Lower 3,792 3,404 2,448 Boundary 90% CI, Lower 3,792 3,404 2,448 Boundary Minimum 3,792 3,404 2,448

TABLE 72 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, 120 mg concomitant verapamil, using the logarithmic model. Moderate Renal Impairment - 20 mg Recommended R, 120 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 11.0 9.9 7.1 90% CI, Upper 3,792 3,404 2,448 14.6 13.1 9.4 Boundary 80% CI, Upper 3,792 3,404 2,448 15.7 14.1 10.1 Boundary IQR Upper 3,792 3,404 2,448 17.5 15.7 11.3 Median 3,792 3,404 2,448 19.5 17.5 12.6 Arithmetic Mean 3,792 3,404 2,448 19.3 17.3 12.5 Geometric Mean 3,792 3,404 2,448 19.6 17.6 12.7 IQR Lower 3,792 3,404 2,448 19.8 14.2 80% CI, Lower 3,792 3,404 2,448 15.8 Boundary 90% CI, Lower 3,792 3,404 2,448 16.9 Boundary Minimum 3,792 3,404 2,448

TABLE 73 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the logarithmic model. Moderate Renal Impairment - 20 mg Recommended R, 240 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 10.3 9.3 6.7 90% CI, Upper 3,792 3,404 2,448 13.7 12.3 8.9 Boundary 80% CI, Upper 3,792 3,404 2,448 14.8 13.3 9.6 Boundary IQR Upper 3,792 3,404 2,448 16.5 14.8 10.6 Median 3,792 3,404 2,448 18.5 16.6 11.9 Arithmetic Mean 3,792 3,404 2,448 18.2 16.4 11.8 Geometric Mean 3,792 3,404 2,448 18.5 16.6 12.0 IQR Lower 3,792 3,404 2,448 18.7 13.5 80% CI, Lower 3,792 3,404 2,448 15.0 Boundary 90% CI, Lower 3,792 3,404 2,448 16.0 Boundary Minimum 3,792 3,404 2,448

TABLE 74 Redosing regimens of rivaroxaban in response to various target AUC values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, 360 mg concomitant verapamil, using the logarithmic model. Moderate Renal Impairment - 20 mg Recommended R, 360 V Logarithmic Redosing AUC Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 3,792 3,404 2,448 9.9 8.9 6.4 90% CI, Upper 3,792 3,404 2,448 13.2 11.9 8.5 Boundary 80% CI, Upper 3,792 3,404 2,448 14.2 12.8 9.2 Boundary IQR Upper 3,792 3,404 2,448 15.9 14.3 10.3 Median 3,792 3,404 2,448 17.8 16.0 11.5 Arithmetic Mean 3,792 3,404 2,448 17.6 15.8 11.4 Geometric Mean 3,792 3,404 2,448 17.9 16.1 11.5 IQR Lower 3,792 3,404 2,448 18.1 13.0 80% CI, Lower 3,792 3,404 2,448 14.5 Boundary 90% CI, Lower 3,792 3,404 2,448 15.5 Boundary Minimum 3,792 3,404 2,448

TABLE 75 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, no concomitant verapamil, using the exponential model. No Renal Impairment - 15 mg Recommended R, 0 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 11.8 11.4 90% CI, Upper 275 268 317 Boundary 80% CI, Upper 275 268 317 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 76 Redosing regimens of rivaroxaban in response to various target steady state steady state C_(max) values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, 120 mg concomitant verapamil, using the exponential model. No Renal Impairment - 15 mg Recommended R, 120 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 9.8 9.5 12.1 90% CI, Upper 275 268 317 15.0 14.3 Boundary 80% CI, Upper 275 268 317 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 77 Redosing regimens of rivaroxaban in response to various target steady state steady state C_(max) values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, 240 mg concomitant verapamil, using the exponential model. No Renal Impairment - 15 mg Recommended R, 240 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 9.3 9.0 11.4 90% CI, Upper 275 268 317 14.4 13.7 Boundary 80% CI, Upper 275 268 317 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 78 Redosing regimens of rivaroxaban in response to various target steady state steady state C_(max) values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, 360 mg concomitant verapamil, using the exponential model. No Renal Impairment - 15 mg Recommended R, 360 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 9.0 8.7 11.0 90% CI, Upper 275 268 317 13.8 13.2 Boundary 80% CI, Upper 275 268 317 15.0 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 79 Redosing regimens of rivaroxaban in response to various target steady state steady state C_(max) values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, no concomitant verapamil, using the exponential model. No Renal Impairment - 20 mg Recommended R, 0 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 7.8 7.6 9.4 90% CI, Upper 275 268 317 11.6 11.2 14.8 Boundary 80% CI, Upper 275 268 317 13.1 12.6 17.0 Boundary IQR Upper 275 268 317 15.9 15.2 Median 275 268 317 19.2 Arithmetic Mean 275 268 317 19.3 18.3 Geometric Mean 275 268 317 19.9 18.9 IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 80 Redosing regimens of rivaroxaban in response to various target steady state steady state C_(max) values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, 120 mg concomitant verapamil, using the exponential model. No Renal Impairment - 20 mg Recommended R, 120 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 6.8 6.7 8.0 90% CI, Upper 275 268 317 9.3 9.0 11.4 Boundary 80% CI, Upper 275 268 317 10.4 10.0 12.9 Boundary IQR Upper 275 268 317 12.3 11.8 15.8 Median 275 268 317 14.9 14.2 19.6 Arithmetic Mean 275 268 317 14.4 13.8 18.8 Geometric Mean 275 268 317 14.8 14.1 19.4 IQR Lower 275 268 317 18.4 17.5 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 81 Redosing regimens of rivaroxaban in response to various target steady state steady state C_(max) values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the exponential model. No Renal Impairment - 20 mg Recommended R, 240 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 6.6 6.4 7.6 90% CI, Upper 275 268 317 9.0 8.8 11.0 Boundary 80% CI, Upper 275 268 317 9.9 9.6 12.3 Boundary IQR Upper 275 268 317 11.7 11.3 14.9 Median 275 268 317 14.1 13.5 18.4 Arithmetic Mean 275 268 317 13.6 13.1 17.7 Geometric Mean 275 268 317 14.0 13.4 18.2 IQR Lower 275 268 317 17.3 16.5 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 82 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, 360 mg concomitant verapamil, using the exponential model. No Renal Impairment - 20 mg Recommended R, 360 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 6.4 6.3 7.4 90% CI, Upper 275 268 317 8.8 8.5 10.7 Boundary 80% CI, Upper 275 268 317 9.7 9.3 11.9 Boundary IQR Upper 275 268 317 11.4 10.9 14.3 Median 275 268 317 13.7 13.1 17.7 Arithmetic Mean 275 268 317 13.2 12.6 17.0 Geometric Mean 275 268 317 13.5 12.9 17.5 IQR Lower 275 268 317 16.6 15.9 80% CI, Lower 275 268 317 19.1 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 83 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, no concomitant verapamil, using the exponential model. Mild Renal Impairment - 15 mg Recommended R, 0 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 10.7 10.3 13.4 90% CI, Upper 275 268 317 Boundary 80% CI, Upper 275 268 317 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 84 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, 120 mg concomitant verapamil, using the exponential model. Mild Renal Impairment - 15 mg Recommended R, 120 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 9.2 8.9 11.2 90% CI, Upper 275 268 317 14.4 13.8 Boundary 80% CI, Upper 275 268 317 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 85 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, 240 mg concomitant verapamil, using the exponential model. Mild Renal Impairment - 15 mg Recommended R, 240 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 8.9 8.6 10.8 90% CI, Upper 275 268 317 13.8 13.2 Boundary 80% CI, Upper 275 268 317 14.5 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 86 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, 360 mg concomitant verapamil, using the exponential model. Mild Renal Impairment - 15 mg Recommended R, 360 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 8.7 8.5 10.6 90% CI, Upper 275 268 317 13.3 12.7 Boundary 80% CI, Upper 275 268 317 14.7 14.0 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 87 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, no concomitant verapamil, using the exponential model. Mild Renal Impairment - 20 mg Recommended R, 0 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 7.3 7.1 8.6 90% CI, Upper 275 268 317 11.4 10.9 14.4 Boundary 80% CI, Upper 275 268 317 12.5 12.0 16.1 Boundary IQR Upper 275 268 317 15.1 14.4 19.9 Median 275 268 317 19.1 18.1 Arithmetic Mean 275 268 317 18.3 17.4 Geometric Mean 275 268 317 18.9 18.0 IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 88 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, 120 mg concomitant verapamil, using the exponential model. Mild Renal Impairment - 20 mg Recommended R, 120 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 6.5 6.3 7.5 90% CI, Upper 275 268 317 9.1 8.8 11.1 Boundary 80% CI, Upper 275 268 317 9.8 9.5 12.2 Boundary IQR Upper 275 268 317 11.5 11.1 14.6 Median 275 268 317 14.1 13.4 18.3 Arithmetic Mean 275 268 317 13.6 13.0 17.6 Geometric Mean 275 268 317 13.9 13.3 18.2 IQR Lower 275 268 317 17.4 16.6 80% CI, Lower 275 268 317 19.9 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 89 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the exponential model. Mild Renal Impairment - 20 mg Recommended R, 240 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 6.4 6.2 7.3 90% CI, Upper 275 268 317 8.8 8.5 10.6 Boundary 80% CI, Upper 275 268 317 9.4 9.1 11.6 Boundary IQR Upper 275 268 317 11.0 10.6 13.8 Median 275 268 317 13.3 12.8 17.2 Arithmetic Mean 275 268 317 12.9 12.4 16.6 Geometric Mean 275 268 317 13.2 12.7 17.1 IQR Lower 275 268 317 16.4 15.6 80% CI, Lower 275 268 317 19.8 18.8 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 90 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the exponential model. Mild Renal Impairment - 20 mg Recommended R, 360 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 6.3 6.1 7.2 90% CI, Upper 275 268 317 8.6 8.3 10.3 Boundary 80% CI, Upper 275 268 317 9.2 8.9 11.2 Boundary IQR Upper 275 268 317 10.6 10.3 13.3 Median 275 268 317 12.9 12.4 16.6 Arithmetic Mean 275 268 317 12.5 12.0 16.0 Geometric Mean 275 268 317 12.8 12.3 16.4 IQR Lower 275 268 317 15.8 15.0 80% CI, Lower 275 268 317 18.9 18.0 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 91 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, no concomitant verapamil, using the exponential model. Moderate Renal Impairment - 15 mg Recommended R, 0 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 10.0 9.7 12.4 90% CI, Upper 275 268 317 Boundary 80% CI, Upper 275 268 317 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 92 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, 120 mg concomitant verapamil, using the exponential model. Moderate Renal Impairment - 15 mg Recommended R, 120 V Exponential Redosing C_(max) Group Target Target Target Dose Dose Dose 1 2 3 1 2 3 Maximum 275 268 317 8.1 7.9 9.8 90% CI, Upper 275 268 317 13.8 13.2 Boundary 80% CI, Upper 275 268 317 14.9 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 93 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, 240 mg concomitant verapamil, using the exponential model. Moderate Renal Impairment - 15 mg Recommended R, 240 V Exponential Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 7.8 7.6 9.3 90% CI, Upper 275 268 317 13.2 12.6 Boundary 80% CI, Upper 275 268 317 14.6 14.0 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic 275 268 317 Mean Geometric 275 268 317 Mean IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 94 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, 360 mg concomitant verapamil, using the exponential model. Moderate Renal Impairment - 15 mg Recommended R, 360 V Exponential Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 7.6 7.4 9.1 90% CI, Upper 275 268 317 12.7 12.2 Boundary 80% CI, Upper 275 268 317 14.1 13.4 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic 275 268 317 Mean Geometric 275 268 317 Mean IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 95 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, no concomitant verapamil, using the exponential model. Moderate Renal Impairment - 20 mg Recommended R, 0 V Exponential Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 6.9 6.8 8.1 90% CI, Upper 275 268 317 11.1 10.7 13.9 Boundary 80% CI, Upper 275 268 317 12.2 11.7 15.6 Boundary IQR Upper 275 268 317 14.6 14.0 19.2 Median 275 268 317 18.2 17.3 Arithmetic 275 268 317 17.5 16.7 Mean Geometric 275 268 317 18.0 17.1 Mean IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 96 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, 120 mg concomitant verapamil, using the exponential model. Moderate Renal Impairment - 20 mg Recommended R, 120 V Exponential Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 6.0 5.8 6.8 90% CI, Upper 275 268 317 8.8 8.5 10.7 Boundary 80% CI, Upper 275 268 317 9.6 9.3 11.8 Boundary IQR Upper 275 268 317 11.1 10.7 13.9 Median 275 268 317 13.3 12.8 17.2 Arithmetic 275 268 317 12.9 12.4 16.6 Mean Geometric 275 268 317 13.2 12.7 17.1 Mean IQR Lower 275 268 317 16.0 15.2 80% CI, Lower 275 268 317 19.7 18.6 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 97 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the exponential model. Moderate Renal Impairment - 20 mg Recommended R, 240 V Exponential Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 5.8 5.7 6.6 90% CI, Upper 275 268 317 8.5 8.2 10.2 Boundary 80% CI, Upper 275 268 317 9.2 8.9 11.2 Boundary IQR Upper 275 268 317 10.6 10.2 13.2 Median 275 268 317 12.7 12.1 16.2 Arithmetic 275 268 317 12.3 11.8 15.7 Mean Geometric 275 268 317 12.6 12.1 16.1 Mean IQR Lower 275 268 317 15.1 14.4 19.9 80% CI, Lower 275 268 317 18.4 17.4 Boundary 90% CI, Lower 275 268 317 19.7 Boundary Minimum 275 268 317

TABLE 98 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, 360 mg concomitant verapamil, using the exponential model. Moderate Renal Impairment - 20 mg Recommended R, 360 V Exponential Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 5.7 5.6 6.4 90% CI, Upper 275 268 317 8.3 8.0 9.9 Boundary 80% CI, Upper 275 268 317 8.9 8.6 10.8 Boundary IQR Upper 275 268 317 10.3 9.9 12.8 Median 275 268 317 12.3 11.8 15.7 Arithmetic 275 268 317 11.9 11.4 15.1 Mean Geometric 275 268 317 12.2 11.7 15.5 Mean IQR Lower 275 268 317 14.6 13.9 19.1 80% CI, Lower 275 268 317 17.7 16.8 Boundary 90% CI, Lower 275 268 317 19.9 18.9 Boundary Minimum 275 268 317

TABLE 99 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, no concomitant verapamil, using the logarithmic model. No Renal Impairment - 15 mg Recommended R, 0 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 11.8 11.4 90% CI, Upper 275 268 317 Boundary 80% CI, Upper 275 268 317 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic 275 268 317 Mean Geometric 275 268 317 Mean IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 100 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, 120 mg concomitant verapamil, using the logarithmic model. No Renal Impairment - 15 mg Recommended R, 120 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 9.8 9.5 12.1 90% CI, Upper 275 268 317 15.0 14.3 Boundary 80% CI, Upper 275 268 317 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic 275 268 317 Mean Geometric 275 268 317 Mean IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 101 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, 240 mg concomitant verapamil, using the logarithmic model. No Renal Impairment - 15 mg Recommended R, 240 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 9.3 9.0 11.4 90% CI, Upper 275 268 317 14.4 13.7 Boundary 80% CI, Upper 275 268 317 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic 275 268 317 Mean Geometric 275 268 317 Mean IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 102 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with no renal impairment where the recommended dose is 15 mg rivaroxaban, 360 mg concomitant verapamil, using the logarithmic model. No Renal Impairment - 15 mg Recommended R, 360 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 9.0 8.7 11.0 90% CI, Upper 275 268 317 13.8 13.2 Boundary 80% CI, Upper 275 268 317 15.0 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic 275 268 317 Mean Geometric 275 268 317 Mean IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 103 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, no concomitant verapamil, using the logarithmic model. No Renal Impairment - 20 mg Recommended R, 0 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 7.8 7.6 9.4 90% CI, Upper 275 268 317 11.6 11.2 14.8 Boundary 80% CI, Upper 275 268 317 13.1 12.6 17.0 Boundary IQR Upper 275 268 317 15.9 15.2 Median 275 268 317 19.2 Arithmetic 275 268 317 19.3 18.3 Mean Geometric 275 268 317 19.9 18.9 Mean IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 104 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, 120 mg concomitant verapamil, using the logarithmic model. No Renal Impairment - 20 mg Recommended R, 120 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 6.8 6.7 8.0 90% CI, Upper 275 268 317 9.3 9.0 11.4 Boundary 80% CI, Upper 275 268 317 10.4 10.0 12.9 Boundary IQR Upper 275 268 317 12.3 11.8 15.8 Median 275 268 317 14.9 14.2 19.6 Arithmetic 275 268 317 14.4 13.8 18.8 Mean Geometric 275 268 317 14.8 14.1 19.4 Mean IQR Lower 275 268 317 18.4 17.5 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 105 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the logarithmic model. No Renal Impairment - 20 mg Recommended R, 240 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 6.6 6.4 7.6 90% CI, Upper 275 268 317 9.0 8.8 11.0 Boundary 80% CI, Upper 275 268 317 9.9 9.6 12.3 Boundary IQR Upper 275 268 317 11.7 11.3 14.9 Median 275 268 317 14.1 13.5 18.4 Arithmetic 275 268 317 13.6 13.1 17.7 Mean Geometric 275 268 317 14.0 13.4 18.2 Mean IQR Lower 275 268 317 17.3 16.5 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 106 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with no renal impairment where the recommended dose is 20 mg rivaroxaban, 360 mg concomitant verapamil, using the logarithmic model. No Renal Impairment - 20 mg Recommended R, 360 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 6.4 6.3 7.4 90% CI, Upper 275 268 317 8.8 8.5 10.7 Boundary 80% CI, Upper 275 268 317 9.7 9.3 11.9 Boundary IQR Upper 275 268 317 11.4 10.9 14.3 Median 275 268 317 13.7 13.1 17.7 Arithmetic 275 268 317 13.2 12.6 17.0 Mean Geometric 275 268 317 13.5 12.9 17.5 Mean IQR Lower 275 268 317 16.6 15.9 80% CI, Lower 275 268 317 19.1 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 107 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, no concomitant verapamil, using the logarithmic model. Mild Renal Impairment - 15 mg Recommended R, 0 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 10.7 10.3 13.4 90% CI, Upper 275 268 317 Boundary 80% CI, Upper 275 268 317 Boundary IQR Upper 275 268 317 Median 275 268 317 Arithmetic 275 268 317 Mean Geometric 275 268 317 Mean IQR Lower 275 268 317 80% CI, Lower 275 268 317 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 108 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, 120 mg concomitant verapamil, using the logarithmic model. Mild Renal Impairment-15 mg Recommended R, 120 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 9.2 8.9 11.2 90% CI, Upper Boundary 275 268 317 14.4 13.8 80% CI, Upper Boundary 275 268 317 IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower Boundary 275 268 317 90% CI, Lower Boundary 275 268 317 Minimum 275 268 317

TABLE 109 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, 240 mg concomitant verapamil, using the logarithmic model.  

   

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TABLE 110 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 15 mg rivaroxaban, 360 mg concomitant verapamil, using the logarithmic model. Mild Renal Impairment-15 mg Recommended R, 360 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 8.7 8.5 10.6 90% CI, Upper Boundary 275 268 317 13.3 12.7 80% CI, Upper Boundary 275 268 317 14.7 14.0 IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower Boundary 275 268 317 90% CI, Lower Boundary 275 268 317 Minimum 275 268 317

TABLE 111 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, no concomitant verapamil, using the logarithmic model. Mild Renal Impairment-20 mg Recommended R, 0 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 7.3 7.1 8.6 90% CI, Upper Boundary 275 268 317 11.4 10.9 14.4 80% CI, Upper Boundary 275 268 317 12.5 12.0 16.1 IQR Upper 275 268 317 15.1 14.4 19.9 Median 275 268 317 19.1 18.1 Arithmetic Mean 275 268 317 18.3 17.4 Geometric Mean 275 268 317 18.9 18.0 IQR Lower 275 268 317 80% CI, Lower Boundary 275 268 317 90% CI, Lower Boundary 275 268 317 Minimum 275 268 317

TABLE 112 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, 120 mg concomitant verapamil, using the logarithmic model. Mild Renal Impairment-20 mg Recommended R, 120 V Logarithmic Redosing C_(max) Target Target Target Group 1 2 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 6.5 6.3 7.5 90% CI, Upper 275 268 317 9.1 8.8 11.1 Boundary 80% CI, Upper 275 268 317 9.8 9.5 12.2 Boundary IQR Upper 275 268 317 11.5 11.1 14.6 Median 275 268 317 14.1 13.4 18.3 Arithmetic Mean 275 268 317 13.6 13.0 17.6 Geometric Mean 275 268 317 13.9 13.3 18.2 IQR Lower 275 268 317 17.4 16.6 80% CI, Lower 275 268 317 19.9 Boundary 90% CI, Lower 275 268 317 Boundary Minimum 275 268 317

TABLE 113 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the logarithmic model. Mild Renal Impairment-20 mg Recommended R, 240 V Logarithmic Redosing C_(max) Target Target Target Group 1 2 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 6.4 6.2 7.3 90% CI, Upper Boundary 275 268 317 8.8 8.5 10.6 80% CI, Upper Boundary 275 268 317 9.4 9.1 11.6 IQR Upper 275 268 317 11.0 10.6 13.8 Median 275 268 317 13.3 12.8 17.2 Arithmetic Mean 275 268 317 12.9 12.4 16.6 Geometric Mean 275 268 317 13.2 12.7 17.1 IQR Lower 275 268 317 16.4 15.6 80% CI, Lower Boundary 275 268 317 19.8 18.8 90% CI, Lower Boundary 275 268 317 Minimum 275 268 317

TABLE 114 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with mild renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the logarithmic model. Mild Renal Impairment-20 mg Recommended R, 360 V Logarithmic Redosing C_(max) Target Target Target Group 1 2 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 6.3 6.1 7.2 90% CI, UpperBoundary 275 268 317 8.6 8.3 10.3 80% CI, Upper Boundary 275 268 317 9.2 8.9 11.2 IQR Upper 275 268 317 10.6 10.3 13.3 Median 275 268 317 12.9 12.4 16.6 Arithmetic Mean 275 268 317 12.5 12.0 16.0 Geometric Mean 275 268 317 12.8 12.3 16.4 IQR Lower 275 268 317 15.8 15.0 80% CI, Lower Boundary 275 268 317 18.9 18.0 90% CI, Lower Boundary 275 268 317 Minimum 275 268 317

TABLE 115 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, no concomitant verapamil, using the logarithmic model. Moderate Renal Impairment-15 mg Recommended R, 0 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 10.0 9.7 12.4 90% CI, Upper Boundary 275 268 317 80% CI, Upper Boundary 275 268 317 IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower Boundary 275 268 317 90% CI, Lower Boundary 275 268 317 Minimum 275 268 317

TABLE 116 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, 120 mg concomitant verapamil, using the logarithmic model. Moderate Renal Impairment-15 mg Recommended R, 120 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 8.1 7.9 9.8 90% CI, Upper Boundary 275 268 317 13.8 13.2 80% CI, Upper Boundary 275 268 317 14.9 IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower Boundary 275 268 317 90% CI, Lower Boundary 275 268 317 Minimum 275 268 317

TABLE 117 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, 240 mg concomitant verapamil, using the logarithmic model. Moderate Renal Impairment-15 mg Recommended R, 240 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 7.8 7.6 9.3 90% CI, Upper Boundary 275 268 317 13.2 12.6 80% CI, Upper Boundary 275 268 317 14.6 14.0 IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower Boundary 275 268 317 90% CI, Lower Boundary 275 268 317 Minimum 275 268 317

TABLE 118 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 15 mg rivaroxaban, 360 mg concomitant verapamil, using the logarithmic model. Moderate Renal Impairment-15 mg Recommended R, 360 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 7.6 7.4 9.1 90% CI, Upper Boundary 275 268 317 12.7 12.2 80% CI, Upper Boundary 275 268 317 14.1 13.4 IQR Upper 275 268 317 Median 275 268 317 Arithmetic Mean 275 268 317 Geometric Mean 275 268 317 IQR Lower 275 268 317 80% CI, Lower Boundary 275 268 317 90% CI, Lower Boundary 275 268 317 Minimum 275 268 317

TABLE 119 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, no concomitant verapamil, using the logarithmic model. Moderate Renal Impairment-20 mg Recommended R, 0 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 6.9 6.8 8.1 90% CI, Upper Boundary 275 268 317 11.1 10.7 13.9 80% CI, Upper Boundary 275 268 317 12.2 11.7 15.6 IQR Upper 275 268 317 14.6 14.0 19.2 Median 275 268 317 18.2 17.3 Arithmetic Mean 275 268 317 17.5 16.7 Geometric Mean 275 268 317 18.0 17.1 IQR Lower 275 268 317 80% CI, Lower Boundary 275 268 317 90% CI, Lower Boundary 275 268 317 Minimum 275 268 317

TABLE 120 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, 120 mg concomitant verapamil, using the logarithmic model. Moderate Renal Impairment-20 mg Recommended R, 120 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 6.0 5.8 6.8 90% CI, Upper Boundary 275 268 317 8.8 8.5 10.7 80% CI, Upper Boundary 275 268 317 9.6 9.3 11.8 IQR Upper 275 268 317 11.1 10.7 13.9 Median 275 268 317 13.3 12.8 17.2 Arithmetic Mean 275 268 317 12.9 12.4 16.6 Geometric Mean 275 268 317 13.2 12.7 17.1 IQR Lower 275 268 317 16.0 15.2 80% CI, Lower Boundary 275 268 317 19.7 18.6 90% CI, Lower Boundary 275 268 317 Minimum 275 268 317

TABLE 121 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, 240 mg concomitant verapamil, using the logarithmic model. Moderate Renal Impairment-20 mg Recommended R, 240 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 5.8 5.7 6.6 90% CI, Upper Boundary 275 268 317 8.5 8.2 10.2 80% CI, Upper Boundary 275 268 317 9.2 8.9 11.2 IQR Upper 275 268 317 10.6 10.2 13.2 Median 275 268 317 12.7 12.1 16.2 Arithmetic Mean 275 268 317 12.3 11.8 15.7 Geometric Mean 275 268 317 12.6 12.1 16.1 IQR Lower 275 268 317 15.1 14.4 19.9 80% CI, Lower Boundary 275 268 317 18.4 17.4 90% CI, Lower Boundary 275 268 317 19.7 Minimum 275 268 317

TABLE 122 Redosing regimens of rivaroxaban in response to various target steady state C_(max) values in subjects with moderate renal impairment where the recommended dose is 20 mg rivaroxaban, 360 mg concomitant verapamil, using the logarithmic model. Moderate Renal Impairment-20 mg Recommended R, 360 V Logarithmic Redosing C_(max) Group Target 1 Target 2 Target 3 Dose 1 Dose 2 Dose 3 Maximum 275 268 317 5.7 5.6 6.4 90% CI, Upper Boundary 275 268 317 8.3 8.0 9.9 80% CI, Upper Boundary 275 268 317 8.9 8.6 10.8 IQR Upper 275 268 317 10.3 9.9 12.8 Median 275 268 317 12.3 11.8 15.7 Arithmetic Mean 275 268 317 11.9 11.4 15.1 Geometric Mean 275 268 317 12.2 11.7 15.5 IQR Lower 275 268 317 14.6 13.9 19.1 80% CI, Lower Boundary 275 268 317 17.7 16.8 90% CI, Lower Boundary 275 268 317 19.9 18.9 Minimum 275 268 317

Additionally, the model system was used to iteratively calculate dosage levels where ranges from 97.5-75% of subjects would have steady state AUC and Cmax levels below the defined safety target levels. These results are included in Tables 123 and 124 below.

TABLE 123 Redosing regimens of rivaroxaban, by percentage of patients below the target steady state AUC values in subjects with no to moderate renal impairment, for varying levels of concomitant verapamil. PBPK Calculated Dosing by Percentile Matching Safety Target Renal State Verapamil Target Levels State Dose (mg) Percentile 3,972 3,404 2,448 Normal 0 75.0% 15 0 90.0% 13 0 95.0% 12 0 97.5% 17 11 120 75.0% 18 16 10 120 90.0% 16 14 9 120 95.0% 15 13 9 120 97.5% 14 12 8 240 75.0% 17 14 10 240 90.0% 15 13 9 240 95.0% 14 12 8 240 97.5% 13 11 8 360 75.0% 16 14 9 360 90.0% 14 12 8 360 95.0% 13 12 8 360 97.5% 12 11 7 Mild 0 75.0% 14 Impairment 0 90.0% 12 0 95.0% 17 11 0 97.5% 18 15 10 120 75.0% 16 14 10 120 90.0% 14 13 9 120 95.0% 13 12 8 120 97.5% 13 11 8 240 75.0% 15 13 9 240 90.0% 13 12 8 240 95.0% 12 11 8 240 97.5% 12 10 7 360 75.0% 15 13 9 360 90.0% 13 11 8 360 95.0% 12 11 7 360 97.5% 11 10 7 Moderate 0 75.0% 13 Impairment 0 90.0% 17 11 0 95.0% 18 16 10 0 97.5% 16 14 10 120 75.0% 15 13 9 120 90.0% 13 12 8 120 95.0% 12 11 7 120 97.5% 11 10 7 240 75.0% 14 12 9 240 90.0% 12 11 8 240 95.0% 11 10 7 240 97.5% 11 9 7 360 75.0% 14 12 8 360 90.0% 12 10 7 360 95.0% 11 10 7 360 97.5% 10 9 6

TABLE 124 Redosing regimens of rivaroxaban, by percentage of patients below the target steady state C_(max) values in subjects with no to moderate renal impairment, for varying levels of concomitant verapamil PBPK Calculated Dosing by Percentile Matching Safety Target Renal State Verapamil Target Levels State Dose (mg) Percentile 275 268 317 Normal 0 75.0% 18 0 90.0% 16 15 0 95.0% 15 14 18 0 97.5% 14 13 16 120 75.0% 15 15 120 90.0% 13 13 16 120 95.0% 12 12 14 120 97.5% 11 11 13 240 75.0% 15 14 18 240 90.0% 13 12 15 240 95.0% 12 11 14 240 97.5% 11 11 13 360 75.0% 14 14 17 360 90.0% 12 12 15 360 95.0% 11 11 13 360 97.5% 11 10 13 Mild 0 75.0% 18 17 Impairment 0 90.0% 15 15 0 95.0% 14 14 17 0 97.5% 13 13 16 120 75.0% 14 14 17 120 90.0% 13 12 15 120 95.0% 12 12 14 120 97.5% 11 11 13 240 75.0% 14 13 16 240 90.0% 12 12 14 240 95.0% 11 11 14 240 97.5% 11 11 13 360 75.0% 13 13 16 360 90.0% 12 11 14 360 95.0% 11 11 13 360 97.5% 11 10 12 Moderate 0 75.0% 17 17 Impairment 0 90.0% 15 14 18 0 95.0% 14 13 17 0 97.5% 13 13 16 120 75.0% 14 13 17 120 90.0% 12 12 15 120 95.0% 11 11 13 120 97.5% 11 10 13 240 75.0% 13 13 16 240 90.0% 12 11 14 240 95.0% 11 11 13 240 97.5% 10 10 12 360 75.0% 13 13 16 360 90.0% 11 11 14 360 95.0% 11 10 13 360 97.5% 10 10 12

Each of the rivaroxaban redosing values specified in the above tables is an embodiment of the methods of the present invention, wherein a patient having the specified renal status, and concomitantly (or not as indicated) administered verapamil, may be re-dosed at the indicated level (or to a level rounded to the nearest mg or 0.5 mg).

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes.

However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as, an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world. 

1. A method of treating a patient in need of treatment with a Factor Xa inhibitor and a calcium channel blocker, comprising: (a) administering about 100 to about 480 mg verapamil daily to the patient; and (b) administering a dose of rivaroxaban to the patient which is less than the dose that would be recommended for that patient if the patient was not concomitantly administered verapamil; wherein after administering the rivaroxaban, the patient exhibits one or more of the following: a steady state rivaroxaban AUC of no more than about 3792 μg·hr/L; a steady state C_(max) of no more than about 317 ng/mL; a risk of major bleeding of no more than about 4.5%; or a prothrombin time of 20-30 seconds.
 2. The method of claim 1, wherein the patient is administered a daily verapamil dose of 120, 240, 360, or 480 mg verapamil.
 3. The method of claim 1, wherein the patient is not renally impaired.
 4. The method of claim 1, wherein the patient is mildly to severely renally impaired.
 5. The method of claim 4, wherein the patient is mildly renally impaired.
 6. The method of claim 4, wherein the patient is moderately renally impaired.
 7. The method of claim 4, wherein the patient is severely renally impaired.
 8. The method of claim 1, wherein the patient has a CL_(Cr) of less than or equal to about 89 mL/min.
 9. The method of claim 1, wherein the patient is has a CL_(Cr) of less than or equal to about 79 mL/min.
 10. The method of claim 1, wherein the patient is has a CL_(Cr) of 60-89 mL/min.
 11. The method of claim 1, wherein the patient is has a CL_(Cr) of 30-59 mL/min.
 12. The method of claim 1, wherein the patient is has a CL_(Cr) of 15-29 mL/min.
 13. The method of claim 1, wherein the dose of rivaroxaban administered in step (b) ranges from about 16% to about 99.5% of the dose recommended for an otherwise identical patient who is not concomitantly administered verapamil.
 14. The method of claim 1, wherein the dose of rivaroxaban recommended for an otherwise identical patient who is not concomitantly administered verapamil is 20 mg, and the dose of rivaroxaban administered in step (b) ranges from about 1 mg to about 19.9 mg.
 15. The method of claim 14, wherein the dose of rivaroxaban administered in step (b) is selected from the group consisting of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, and about 17.5 mg.
 16. The method of claim 1, wherein the dose of rivaroxaban recommended for an otherwise identical patient who is not concomitantly administered verapamil is 15 mg, and the dose of rivaroxaban administered in step (b) ranges from about 1 mg to about 14.9 mg.
 17. The method of claim 16, wherein the dose of rivaroxaban administered in step (b) is selected from the group consisting of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, and about 12.5 mg.
 18. The method of claim 1, wherein after administering the rivaroxaban, the patient exhibits two or more of the following: a steady state rivaroxaban AUC of no more than about 3792 μg·hr/L; a steady state C_(max) of no more than about 317 ng/mL; a risk of major bleeding of no more than about 4.5%; or a prothrombin time of 20-30 seconds.
 19. The method of claim 1, wherein after administering the rivaroxaban, the patient exhibits three or more of the following: a steady state rivaroxaban AUC of no more than about 3792 μg·hr/L; a steady state C_(max) of no more than about 317 ng/mL; a risk of major bleeding of no more than about 4.5%; or a prothrombin time of 20-30 seconds.
 20. The method of claim 1, wherein the condition is selected from the group consisting of: reducing the risk of stroke and systemic embolism in patients with non valvular atrial fibrillation, treating deep vein thrombosis (DVT), treating pulmonary embolism (PE), reducing the risk of DVT, and reducing the risk of PE, the prophylaxis of DVT which leads to PE in patients undergoing knee or hip replacement therapy, and the management of essential hypertension. 